TABLE 21; comm-s

INTRODUCTION
PCB Fact Index
Workplace Precautions Health Effects

1936 Public Health Service recommendation for
periodic examinations for systemic poisoning of workers
exposed to PCBs

1936 complaints of digestive disturbances, burning of
the eyes, impotence and hematuria following exposure to
PCBs, and recommended precautions -

1943 industrial medicine publication advocating a)
instruction to workers as to the toxic nature of 
b) necessity of pre-employment and periodic physical
examinations: and,c? recommendations for engineering
control measures

1944 detailed recommendations for personal hygiene for
workers exposed to PCBs, including the admonition that
workers should avoid excessive use of alcohol, by Union
Carbide

Health Effects

Toxic acquired caused by PCBs

March 18, 1975, report from Monsanto to Westinghouse
that PCBs can cause severe health problems in humans

23 adverse health of victims of the Yusho PCB
poisoning, with supplemental listing of subjective
complaints

fJuly 17, 1986, medical report by Ellen K. Silbergeld,
on health effects caused by exposure to PCBs,
furans, and dioxins

12

I6

 

10"
.exPOSed toiPCBs at th# Westinghouse plant in

.11.

1'12.Health effects caused by PCBs described by the United

Statescenera? Accounting Office, and a summary of 
regulations under the T0xic Substances Control Act of
1976 (TSCA) 



December, 1980, reSponse tabulation for workers

 

Bloomington, Indiana, baped on a 1977 NIOSH survey

?ay,?1987, summary of caused by exposure to
PCBs with identification of high-risk sub?populations

. i 
Four documents issued EPA describing health
effects of PCBs

Cancer

December 29.11987, confirmation official that.

PCBs are a probable-human carcinogen . 

August 10, 1987, study of evidence that PCBs produce
cancer in humaps 

August 27, 198?, comparison of animal?based expected and.
human observediCancer risks;associated with PCB exposureI

I

Biochemical Mechanisms

April, 1985, summary describing nine biochemical
mechanisms implicated in the induction of PCB toxic
effects 
. 1
PCBs: January 1988, report on the biochemical basis
for toxicity 1 .



Biphenylenes

 

1986 identification of biphenylenes
as extremely toxic'byproducts from the burning
of PCBs

- 19.

20.

Monsanto Mortality Study

Unpublished 1979 mortality study of PCB workers at the
Honsanto plant in Sanget, Illinois, showing that.22.88
deaths were expected and 30 were observed

Health Survey Form

Form for preliminary history and survey of health
or conditions for individuals exposed to PCBs

I

- -

02



r?"z
off



 

INTRODUCTION

 

-

The enclosed materials. which date from 1936 to 1988,
discuss necessary precautions to safeguard workers from adverse
health effects c.aused by PCBs, 'health and conditions
caused by PCBs, evidence t-hat PCBs cause cancer in humans, the
mechanisms of biochemistry implicated in the induction of PCB
toxic effects and other matters relating to health concerns.
care, and treatment of individuals exposed to pass.

The dedicated and tireless efforts of Deirdre B. Poster, RN,
FNP, PA-C. Joseph R. McKenna, Stuart A1 Curry, David E. Schalk,
and Mick Harrison in compiling this text are deeply appreciated.
It is estimated that this compilation represents a work effort of
approximately 1400 hours by these individuals.

It is hoped that the materials will be of interest to

individuals exposed to PCBs, physicians, scientists, government

officials, and others. i 3

John R. Foster

1 341 Sample Rd.
Bloomington, IN 47401

15 January 1988

_17?

 





r. 

r"

 

 

. PCB Pact Index

 




1
I
PCB stands for Bipheny1.A PCB is a
molecule composed of ?three chemical elements: hydrogen;
carbon- and chlorine. !Furans, dioxins, and related
compounds are contaminants of PCBs and/or the byproducts of
burning PCBs. Furan and dioxin molecules are similar tolPCB

 

molecules. A furan molecule is the same as a PCB withi the

addition of an oxygen atom, a dioxin molecule is the same
as a PCB with the addition 'of two oxygen atoms.

PCBs are the only chemical that were ever specifically
banned by the Congress of the United States. This occurred
in 1976. i


PCBs are a man-made chemical. PCBs do not\appear naturally.
A11 PCBs made in the United States after 1935 were
manufactured by Monsanto Company at its plants in Anniston,
Alabama, and Sauget, Illinois.

PCBs enter the human body'by three routes: breathing; skin
absorption: and ingestion. 1
The most severe exposures to PCBs occurred in the workplace.
It is estimated that 12,000 workers were potentially exposed

. to PCBs annually from 1970 to 1976. (The total number of

 

workers exposed to PCBs from 1935 to 1976 has never been
calculated.) Adverse health effects from chemicals are
generally more severe with higher doses. The individuals
with the highest exposureihave the most critical medical
needs. There is a need for government agencies, such the

- National Institute of Occupational Safety and Health (NIOSH)

and the Centers for DiseaselControl (CDC). with expertise in

-PCB toxicology to provide medical protocols to local

physicians to assist them in the diagnosis and treatment of
workers with known exposure to PCBs.

Workers at the Westinghouse capacitor plant in Bloomington,
Indiana, who worked in the area of the plant where the
capacitors were filled with PCBs, had an average blood PCB
level of 502 part-s per billion. They were tested in 1977.
These workplace levels compare to the average level in the
general population of 5 - 8 parts per billion.

 

 

10.

i




 

'latency periods.

PCBs stay in the blood and fat of an individual longer than

- many other chemicals. PCB levels in the blood and fat

gradually reduce. Example: a worker had 336 parts per

9 billion PCB in his blood in 1977, and 8.76 parts per billion

in his blood in 1985.

As has been observed with other chemical exposures, the
health effects from PCB exposure have'the potential for 10ng

 

IMarine veterans of Vietnam, exposed to Agent Orange

(contaminated with a 58 percent higher rate of
lung cancer than Marines who did not go to Vietnam, and had
a 110 percent higher rate of non-Hodgkin?s (a
category of cancers of the system). These Marines
also had potential exposure to herbicides, arsenicals,
dapsone, and certain viruses.

-The proposed safe level for PCBs in water is 0.00079 paEts I
lper billion. By comparison, the safe level for arsenic is

0.022 parts per billion. -

i
I

 - Schwartz, Louis, M. "Skin Hazards in American Industry Part No. 229
Public Health Bulletin, U. S. Treasury Department, Public Health Service 
m. EEptember, 1936). 

 

 

1' 

9. Workers in chlorinated naphthalenes and diphenyls should be periodically
examined for of systematic poisoning 

Sohwartz, Louis(Senior lSurgeon, U. S. Public Health Service, New York,

N. "Dermatitis from Resins and Waxes"; 26 American Journal of Public
H__e__alth 586 (June, 1936). . i i



In addition to these skin lesions, of systemic poisoning have
occurred among workers inhaling these fumes. Those working with the chloro
diphenyls have complained of dige?stiVe disturbances, burning of the eyes,
impotence and hematuria. The latter developed among a number of men
making amino diphenyl, which is used inlthe manufacture of a rubber antioxidant.
Cases of death from yellow atrophy of the liver have been reported among workers
expoSed to the fumes of the chloro naphthalenes.

1'

Patch tests performed with' Halowax and with the chloro diphenyls
have yielded negative results. The skin lesions probably result from the-
mechanical plugging up of the follicles of the skin with the waxes as the fumes solidify
on the skin.?I The chlorine present in the waxes may have an irritating effect on
the plugged follicles and cause suppurationn 

i . 
PREVENTION I

1. The protection -of the workers from the irritating chemicals that
compose the resins and waxes from the resins and waxes themselves. To do this,
the process should be totally enclosed. If this is not possible, hoods with suction
exhaust should be so placed over Open processes that dust and fumes are pulled away
from the worker and Out of the room. 

2. The workrooms themselves should be ventilated by intake and exhaust
fans to remove dust and fumes.

 

1
6
I

3. The ?oors, walls, and ceilings should be washed- down at frequent
intervals to keep them free of dust. i

4. Two lockers should be fml?nished to each worker. One. for his street
clothes and one for his work clothes. The Ilockers for street clothes and work clothes
should be in separate rooms, with the shower baths between the locker rooms. The
worker coming to work .enters the locker room for the street clothes, takes them'
off, and puts them in the locker and. goes into the locker room where his clothes
are kept and dons them. From this room he goes to the workrooms through a
connecting door. At the end of his shift, he goes through this door to the work clothes
locker room, takes off his work clothes and leaves them on the floor or bench to
be washed and then goes to the shower liaths and bathes and dries. Then he goes
to the street clothes locker room, puts on his clothes and goes out of the door leading
to the street. It has been estimated at one plant where suCh a system was instituted
that 6 cents a day per worker will take care of furnishing clean work clothes each
day.

I have recently seen the wife and child of a worker who had developed
'comedones and pustules from contact with his work clothes which were saturated
with .halowax and which he was accustomed :to wear at home. L. S.

PM


 

 

 

5. New workers who are hypersensitive, but have only mild eruptions,
should be given protective ointments and clothing and kept at work for about 3 or
4 weeks with the hepe that they will develop an immunity or become "hardened."
If this does not occur, they should be taken 'off the job.

6. New applicants for jobs should be carefully examined for skin diseases
and those found to have them should not be 'employed.

7. There should be. periodic .medical examination of workers to detect
cases of dermatitis and workers in chlorinated naphthalenes and diphenyls 
should be periodically examined for of systemic poisoning.

8. Laws should be passed making it compulsory for factories where
there are skin hazards to adopt these measures. (pp. 591-592)

 

Pg. 3

 

i

i


Gre'e'nburg, Leonard, "Chlorinated Naphthalenes a?nd Diphenyls 12:8 Industrial
Medicine 520 (August, 19.43The foreman of all departments where this material is handled should be apprised
of the toxic nature of the material and instructed in safe handling procedures.! These

men should make it their duty to check up oin the workers in their- departments and instruct 
them in safe practice.'

4. Pre?employr?nent and periOdic phys?cal examinations should be made of all exposed
workers. These should include the taking of a full clinical history, with special emphasis
on gastro-intestinal disturbances and dermatitis. In addition, the skin should be carefully
examined periodically and the more ireliable liver 'function tests performed.
Gastrointestinal complaints developing in 'a worker at any time should be a signal for
an immediate medical check-up. A history of liver disease, jaundice, or antisyphilitic
treatment should autOmatically exclude a worker from jobs involving a possible toxic
exposure. Pregnant women shOuld not .be Zemployed where there is a possible exposure
to the chlorinated waxes. i


5. Engineering control of plant operations cannot be overemphasized but specific
recommendations are not applicable to .all cases. It would be wise for a plant using. this
class of materials to check their control measures with the state industrial hygiene agency,
the ins)urance carrier and some competent consultant before occupational disease'occursCranch, A.G., "Chlorinated Compounds -- Precautidns in flandlin" 13:1
Industrial Medicine (January, 1944). - 

 

 

CHLORINATED COMPOUNDS

-Precautions in Handling-

 

Dr. A. G. Cranch, Direct of Union Carbide 6: Carbon Company's Toxicological
LabOratory, submits the following precautions for handling certain chloro-naphthalene,
chloro?diphenyl (PCBs), and related chlorinfated compounds. These were developed,
under his direction, by the_Halowax, Products Division, (30 East 42nd St., New York),
and are presented here not only for their value in avOiding harmful effects from these
chlorinated materials but also on account of the applicability .of these precautions
to operations where. analogous materials are employed. The practice of the

manufacturer in distributing this information to all of its customers, and to health

agencies generally, is to be. commended.
i i

i i
Personal Hygiene: All unnecessary prolonged contact with these
materials should be avoided. This as to vapors from the heated material, and exposure
to the-Solid. i
There should be a complete change from street clothes to working
clothes before going to work. Work clothes should be supplied including such items
as starched and laundered cover-ans of light color and close Weave; .socks; caps; and
underwear (preferably union suits with long sleeves and legs). Gloves and aprons should
be buttoned at the wrist. Cover-alls should beibuttoned at the neck. Fresh work clothing
should be supplied for regular operators twice a week or oftener, daily in hot weather.
It should not be taken home for laundering. Provision should be made by the employer
for this. If exposure is occasional or intermittent, a different schedule might be
warranted.

Separate lockers should be provided for street clothes and work clothes,
which should never be kept in close contact in the same locker.

It is essential that face and hands be washed before eating, and that
a shower be taken on quitting work. It is recommended that the daily shdwer should
be supervised to make certain that washing '5 thoroughly carried out before resuming
street clothes and leaving the work place. I

A suitable skin cleanser should be provided. Strong solvents or soaps
containing mineral abrasiVes' should be avoided. Powdered soap containing a corn meal
abrasive is probably themost suitable soap, but there are a number of recently developed
cleansers based on sulfonated vegetable oil, which may prove to be very satisfactory.

 

Pg. 5

 



-used on the face.

 

Protective creams offer an additional protection when applied to the
face and hands, or to other exposed skin surfaces. These should be applied before
work and renewed at least once or oftener, if necessary, through the day. Contact
of soiled hands with the face should be avoided. Solid waste or rags should not be

 

Employees should be cautioned as to the effects of excessive use of
alcohol, exposure to chlorinated hydrocarbon solvents, or continued exposure while
under medication involving the use Of the heavy metals, such as arsenic or bismuth.
They should also report at once any evidence of dermatitis, or digestive or liver
disturbance. 



 



 


'I'v

rel-7. 

 

Isselbacher, Adams, Braunwald, et al, eds.; Harrison?s Principles of Internal Medicine,
Ninth Ed. (1980).



 

Toxic acquired resembling PCT has occurred in individuals accidentally
exposed to hexachlorobenzene, biphenyls, tetrachlorodibenzo?p-dioxin
(TCDD), and other hydrocarbons. Moreover, several instances of benign
or malignant primary tumors of the liver have been observed in association with PCT.
(Chapter 96, at p. 499)



 

Pg. 7

 

 

March 18, 1975 answers from W.-B. Papageorge, Manager, Product

Acceptability, Specialty 6: Process Chemicals, Monsanto Company,

St. Louis, Missouri, to Seven questions from. Dan A. Albert, Staff

Supervisor, Personnel Relations, Westinghouse Electric Corporation,
South Boston, Virginia, about suspected or potential health problems

caused by PCBs (on the following pages).



 

Pg. 8

2.

Question: Does Inerteen have permanent effects on the
human body? If so,'uhat type of permanent damage and
how long a period of.time does it take for this to
develop? If not, explain why, if possible.

The biphenyls in Inerteen can have permanent
effects on the human body.

The length of time or'period of exposure necessary to develop
depends on the degree or amount of exposure. In general,
a single exposure for a.feu'minutes to atmospheric concentrations
that cause irritation to the eyes and/or respiratory tract.would
not be expected to cause either the skin eruptions or demonstrable
liver injury. The problem arises from repeated and prolonged
exposure to atmospheric concentrations in excess of the accepted
Threshold Limit Levels or repeated and prolonged skin contact.

The biphenyls have not been recognized as skin
'irritants' in the same sense that caustic materials or many
organic chemicals are irritants. Because of their 'solvent'
action in removing the natural fats and oils from the skin leading
to drying and chapping, repeated and prolonged skin contact
should be avoided. -

When the biphenyls are mixed with other chlori-
nated hydrocarbons; the mixture may be classified as a skin
irritant.

The potential toxic effects in humans from excessive exposure
to biphenyls include injury to the liver and
chloracne. In animals, the liver effect is demonstrated by
increased liver weights and injury to cellular tissue. Although
chloracne is difficult to evaluate in animals, in humans, this
takes the form of comedones (large blackheads with typical acne
pustules) and may be an external of over exposure pre-
ceding serious liver injury. - 

Animal data and human experience indicate that the toxic effects
are similar whether exposure results from ingestion, inhalation
of vapors, or absorption.of the liquid material through the un-
broken skin. 

Hygienic Guide:Series - 'Chlorodiphenyls' attached.)

Onestion: Several hourly employees have mentioned recently
that many chemicals such as Inerteen cause sterilization
after prolonged use. Is this true?

There is no evidence that biphenyls' cause
"sterilization? in humans. pg_9

 

 

3- Question: Since Inerteen affects birds and other animals, 

if there is no real effect! to human beings, how do
you explain it to employee's in such a way that they
will understand why it can: kill a bird and not a hmnan?

There is a potential real effefct to humans - including death -
as discussed in the answer to Question 1. . -

Due

to differences in metabolism of food (and food contami-

nants) in birds and humans (and particularly the difference
in the reproduction process in: birds and manuals - including
humans), birds are particularly sensitive to many chlorinated
hydrocarbons including biphenyls.

Question: If an employee spills Inerteen on his clothing

and later takes -the clothing home to be washed with' other
clothes, will this have any effect on him or his family}
andshould he carry his clothes home to be washed? .

- There should not be.any effect on an employee or his family

from home laundering of work clothing. If washed with other.
clothing, there may be residual odor of the chlorinated
hydrocarbons in the clothing.

Question: Employees carry Iner?teen home on the soles of their

shoes and complain quite a bit about the effect Inerteen
has on wearing out of their shoes. Is this a serious i
problem? Will Inerteen in the soles and leather of shoes,
over a long period of time, have an effect on the feet and
skin since the shoe is the. only protective equipment we
wear on' our feet and the Inerteen penetrates through the
leather. . 

There should not be biphenyl on the floor for
workmen to contaminate their shoes to carry home. The plasti-
cizer or solvent action will destroy or. shorten the life of

,the

shoes.? More importantly, the wearing of contaminated

shoes could lead to absorption ?of the liquid through the soles
of the feet as through any other unbroken skin surface.

Question: There is one employee in our plant who had no pro.-

blem whatsoever with Inerte'en years ago. After six years
of using, now when heworks?; in Inerteen (which is a part

of his job) he develops a swelling on the inner bicep of'his
left arm, only in one location. Could this be from Inerteen
or not? It goes away as soon as he gets out of the 'Inerteen.

is similar to the swelling after taking an injection.

7

Pg. 10

 

7.

We do not believe there can be any association between 
"a swelling on the inner bicep?l of the arm and exposure to
biphenyls.

 

Question: Are there hand cleaning solvent materials that
we should be'using when wo king in Inerteen to coat
our skin before working in it and to wash it off
after 'we finish working in it? Please give your
recommendation. Our employees working in Inerteen
are not able to use glov'es? Since it is an assembly

area. Even if they could, the Inerteen would destroy
the protective glove. . - .

 

We assume the question refers to the use of "Barrier Creams?
rather than a ?hand cleaning solvent" .

There'are a number of barrier creams available to protect
workers against water insoluble! solvents. Probably the most 
effective include silicone "5 provide an impenetrable shield".

A problem with such creams is that they may offer a false
sense of security. 

Proper use includes a discipline which requires liberal appli-
cation at the beginning of a work shift and after each washing
of the hands during the work day. 

 

Pg. 11

 

 

a It . Hit-m: 1-81-1921
. 655% Faeseargn and "mew
Deva-25091113111 .-

DRINKING CRITERIA FOR 
BIPHENYLS 

 

 

a Pfepared War

I arms a mums um:

. 

1.- Pmparea? by .

Environmental Criteria and
1? Assessagem Of?ce -
Cincinnati OH 45263

W: 00150? CITE on 

- i

03111:!

Th1: dumnt 1s a gunman: dra?t. It has at been 10111111: retreated

. by the 11.5. (autumnal Putt-c1191! Agency and sauna not at stage he
- construed to represent #1139191?. It 1: 51:11:; ?mum for. cam-cuts

01: 1t: ?curl! 8" 

3 .mnonu mm
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m??gimp-.2: . 9-5?433:; 514-2 - .- . 
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Alb-1'71 15:91?? 13? Eb. - .- -5-: 3153 warn-M313. 1555-2-31- .o 515:. 

 

a.
- 3.. 

"It! 

lime-at museum or supra: 01 rum and renun-

 

 

 

 

'Sgwtus - - Hales fell-ales
(0-091 ?.1001
I
lack broun pig-entatica of nails 00.1 15.0
listinctire am f0111c1es I 56.0
Increased sweating at pains 50.6 55.0
lcnelite skin eruptions I 01.0 02.0
Red plaques on 1100s I 20.2 16.0
Itching 02.1 52.0
Pigmentation of skin 15.! 12.0
Smiling 0f "lbs 20.2 01.0
Stiffeneg-soles in feet and pain: or hands an 23.0
Pigaentea mucous leubrane 55.2 41.0
Increased discharge 00.0 03.0
Hypereuia 0f conjunctiva 10.0 11.0
transient visual disturbance 56.2 55.0
Jaundice 11.2 11.0
of upper eye1ids 11.9 14.0
feeIing cf ueatness 50.1 52.0
lanbness in limbs 32.6 10.0
fever 10.0 10.0
Hearing difficulties 10.0 19.0
Spas. of 1110s 0.0
Headache 30.: 3.0
Vonitin? 23.0 10.0
01mm 19.1 11.0
?Sources'laratsune et a1.. 1969
02:00 11-10 00mm

 

Pg.13

_d
_l

I PCBS: 


:o .-

 

 

VULUME 59, FEBRUARY 1985



 

 
L. 

:3

 

Table 2. Subjective complaints on the'?rst visit (358 cascsl.
I .

 

 

 

 

 

 

No. of
Complaints patients 9
Disturbance of vision. easy fatigability 183 51.4
Soreness. irritation of the 1'67 18.8
Headache. dizziness: ?78 21.9
Malaise 133 37.3
Cough 50 1-1.2
Reduced appetite 1? 4.9
Soreness. pain or swelling of the limbs. joints 24 6.8
Neck pain. lumbago 56 15.6
Numbness of the limbs 13! 37.3
'Pruritus 127 35.6
Abnormal menstruation 20 10.7?
of female patients'.
Table 3. Subjective complaints (2-18 cases).
No. of
Complaint patients 
Increased discharge 182 73.4
Edema of eyelids 152 61.3
Vision disturbance 89 35.9
irritation of eyes 5 7 2.8
Headache. dizziness 62 .50
General malaise 107 43.1
Reduced appetite 30 12.1
Soreness. pain of joints. muscles 51 20.6
Numbness of limbs 78 31.5
Nausea. abdominal pain. diarrhea 18 7.3
Pruritus 35 1-1.1
Hyperidmsis of palms. soles 11 4.4'
Cough 25 10.1
Abnormal menstruation 14 11.2?
Othersh -- 21 8.5

 

'11. 2% of female patients

I?lncluded decreased bodyweight (3). lumbago (3). dryness of
mouth (2). tinnitus (2). leg edema (1). neck pain (1). exophthalmus
constipation (1). gynecomastia (1) and diabetes mellitus (1).

 





Pg. 15

 



 

 

REPORT DATED JULY 1986 FROM

EXCERPTS FROM 
ELLEN K. SILBERGELD, .

There is general scientific consensus that PCBs, aroclors, chlorinated
benzenes and their combustion products (?hlorinated dibenzofurans and chlorinated
dibenzo?p-dioxins, and respectively) are highly toxic to humans (for
recent consensus documents of these substances, see health assessment and other
documents prepared by EPA in 1982, 1983, 1984, 1985, 1986; have served ,as an expert

peer reviewer for most of these documents). 3

Human exposure to PCBs "and aroclors are associated with a range of severe
health effects, including pulmonary dysfunction, peripheral nervous system damage,
CNS damage, hyperlipidemia (and hyperchlolesteremia), dermatotoxicity, immune
suppression, reproductive disorders, liver toxicity, dematotoxicity, and increased risk
of cancer. For these reasons, PCBs have been banned from use in the US since 1977,
and similar restrictions are being imposed in most European countries and Japan (See
OECD directives of PCBs, 1984 and 1986). i

Extraordinary risks are associated with operations which involve contact
with PCBs, arocl'ors, and 'chlorinated benzenes under conditions where these substances
are heated. Heating of these substances in the presence of oxygen is knewn to yield
and including the highly toxic isomers 2, 3, 7, 8-TCDD and
2, 3, 7, 8-TCDF. This chemical reaction can be demonstrated in the laboratory (see
work by Rappe and others) and has been documented in the field, when salvage operations
or fires have involved oxidation of these substances (see reviews of' DIOXIN 85 and
APHA 1985 symposia, in both of which I participated as an invited Speaker).

and are among the most toxic substances yet studied. They
are acutely toxic, causingllethality and an irreversible wasting in many test
species; they are immune suppressants, hepatotoxins, neurotoxins, dermatotoxins,
agents, teratogens, and carcinogens in many species. In humans,
exposures to have been associated :with immune dysfunction, neurotoxicity,
hepatotoxicity, and increased ineidence of certain cancers. are-
associated with serious reproductive effects, dermatotoxicity, and hepatotoxicity,
in two incidents in Japan and Taiwan where concurrent exposure to aroclor-like mistures
and occurred accidentally. 

Toxic effects in humans and animals have been described in situations where
these substances are burned; near a?wire reclamation facility, described
a range of toxic effects, and in firefighters aind others exposed to combustion products
from PCB transformer fires, Schechter, Rappe, Melius, and others have reported
hepatotoxicity, melanoma, dysfunction, as well as elevated blood
lipids. 


The neurotoxicity which is described in the medical materials related to
nuclear magnetic imaging of the brain and the electrophysiological studies is consistent

Pg. 16

 

I
I

 

with the known toxicity of these substances. That is, demyelination is associated with
exposure to PCBs, aroclors, and because of their actions as
agents. Because of the importance of cellular heme in
the myelinating cells of the CNS and PNC (glia and Schwann cells), disruptionlor
inhibition of heme is known to result in pathological reactions in these cells
and loss of their functional association with nerve cells and axonal processes.
Demyelination has functional consequences which are frequently reflected in
electrophysiological abnormalities, since intact myelin is required for nerve cells to
propagate membrane potential changes and to transmit information from cell to cell.
Thus the findings of abnormal electrophysiological responses are also consistent with
MN examinations (see also work by Singer).

The significance and clinical expression of such neurotoxicity depends upon
the location of demyelination (in the or whether it involves sensory or motor
nerves in the PNS, as well as upon the extent and duration of demyelination. Extensive
and chronic demyelination can result in neuropathy, through the death of neurons and
axonal processes after the loss of physiological association with nyelinating cells (see
Spencer and Schaumberg, Handbook of Clinical and Experimental NeurotOxicology) I

Assuming that these neurotoxic signs are in fact associated with exposure
to PCBs, aroclors, chlorinated benzenes and their combustion products, this indicates
that the exposure was in fact prolonged and relatively high. At such levels of exposure,
other toxic effects have probably also occurred in these persons, including
dermatotoxicity, hepatotoxicity, hyperlipidemia and/or hypercholesteremia, immune
dysfunction, and increased risk of cancer. 'Hyperchloesteremia and hyperlipidemia,
which have been reported in. several groups of electrical workers (and in persons exposed
to transformer fire byproducts at Binghamton NY) are risk factors for heart disease.
Increased incidence of coronary heart disease may also be expected in this group.
Expression of carcinogenic effects, and the ability to detect this increased risk, Iis
highly dependent upon the length of time which has elapsed between exposure and
observation, and upon the number of persons studied. However, reports 'by Brown and
colleagues at NIOSH indicate that increased incidence of cancers can be expected
to occur in occupational cohorts within 15-25 years after exposure. Reproductive
effects may also have occurred in this group, particularly in women: and in fetuses
carried by exposed women. I

Because of the complex range of effects associated with these substances,
as well as their demonstrated activity as i'mmunotoxins and promoters, a range of
health effects can be expected to occur in these people. That is, damage to the immune
system may be detected upon proper clinical tests as alterations in cell- or
h'umoral - mediated immune response, or more generally as increased incidence or
severity of infectious disease (including viralIdisease). As promoters, 
and P035 interact withinitiating carcinogens, such as mutagens, to increase the outcome
of cancer; promoters- may not have any specific site of action, but? may rather increase
the incidences of many types of cancer whose site of incidence depends more upon
the initiating event than upon subsequent promotion.

1
I 1
Pg. 17

GAO



United States General Accounting Of?ce 1

Report to the Chairman, Subcommittee on
Environment, Energy, and Natural I
Resources, Committee on Government

Operations, House of Representatives

 

May?1987



 

TOXIC SUBSTANCES

 

Abandonment of PCBS 
Demonstrates Need for 
Program 
Improvements

 

 

Pg. 18 -





i

.J



?1
?1




I









 



 

PCBs are toxic chemicals that can cause serious health and environmental
problems. In well-documented tests on laboratory animals, PCBs have been shown
to cause reproductive disorders, birth defects, gastric disorders, skin lesions, swollen
limbs, cancers, tumors, and and liver disorders. The dangers from relatively high
exposures to PCBs were tragically demonstrated in 1968 when about 1, 300 people in
Yusho, Japan, used rice oil that had been accidentally contaminated with P035 leaking
from a transformer. The victims developed a variety of ailments characterized as
"Yusho Disease,? including skin lesions, discharges, abdominal pain, and reproductive
and nervous system disorders. Evidence of an11ncreased rate of cancer has been observed
in the Yusho victims who have died since 1968. As a result of the Yusho tragedy, .the

Japanese government virtually banned the production, import, or export of PCBs in
1972. 9)

tootteoottettee 

.1 I

PCB Regulation Under TSCA

Because of concerns about the health effects of PCBs and the growing
evidence of its presence and persistence in the environment, the Congress in 1976
passed the Toxic Substances Control Act banning further manufacture of the chemical
and directed EPA to prescribe regulations for handling PCBs still in use, their eventual
phase-out, and subsequent disposal. The Congress directed EPA to issue regulations

governing their continued use and eventual disposal. These regulations were first issued
in 1978 and revised in 1979.

I
Specifically, TSCA provides EPA with the authority and responsibility to
protect human health and the environment Efrom unreasonable risks arising from the
manufacture, processing, distribution, use, or disposal of PCBs, Section 6(e) of TSCA
prohibits the manufacture of new PCBs, prohibits the processing, commercial

distribution, and use of all PCBs in other than a totally enclosed manner, and requires
prOper disposal of PCBs. .

EPA's PCB regulations outline specific disposal requirements. Although
these requirements do not Specifically address abandonment of PCBs, EPA has
interpreted the regulations to conclude that abandonment constitutes imprOper disposal
and, therefore, violates PCB regulations. Other EPA PCB regulations also require
(1) marking high PCB concentration equipment and regulated PCB waste with specified
labels, (2) destruction or disposal, where appropriate, of PCBs within 1 year of their
being removed from use and placed in storage, (3) storage of PCB items in curbed,
secure, enclosed structures, and (4) recordkeeping by PCB generators/owners and disposal
facilities to document PCB disposal.

-Pg. 19

a 




I





 

i
. i

PCB regulations provide deadlines for the removal .of most in?use capacitors
and transformers containing PCBs and limit time for sterage for.disposal to 1 year.
EPA allowed the continued use of PCBs in electrical transformers and capacitors 'wlien
EPA determined such use did not pose an unreasonable risk; however, EPA specified
that all capacitors except those in isolated areas be removed from service by October
1988, and transformers of a certain size in 'or near commercial buildings be removed
by October 1990. For those handlers of PCB's removed from service, one of the most
crucial regulations is the 1-year storage requirement, which is intended to assure that
PCBs are ultimately disposed of within a reasonable period of time. Specifically, the
requirement states that (1) P035 stored before January 1, 1983, were to be removed
from storage and disposed of before January 1, 198.4, and (2) P035 stored after January
1, 1983, are to be removed from storage and; disposed-of within 1 year from the date

they were first stored. Hundreds of millions of pounds of PCBs will, therefore, require
both proper and timely disposal. (pp. 10-11) 

 

 

Pg. 20

an

 

 

Cross-Sectional Medical Survey of a
Group of Workers Occupationally Exposed
To Hiphenyls (Peas)

at an Electrical Equipmenc Manufacturing Plant


I

 

Alexander B. gSnithl
Joanne Schloemer1
Larry K. Lowryz
Anthony H. Shallvood2
Robert H. Ligo1'4
Shiro Tanakal
Killian Stringetl
Hark .?Jonesl"5
Charles J. Clueck3

v.5. Department of Health and Human Services
Public Health Service
Center for Disease Control
National Institute for Occupational Safety and Health
Division of Surveillance. Hazard Evaluations and Field Studies
Cincinnati. Ohio $5226

and 

Lipid Research Center
University-of Cincinnati Medical Center
Cincinnati. Ohio 45267

December. lien


1

I

:2


 

Pg. 21

if]

.3

 

 

 

I

A history of irritated or burning eyes, of unusually poor appetite, of
unusual dark patches of skin, and of high blood pressure, were significantly associated
with increasing serum level (dichotomized as less than 200 ng./ml., greater
than or equal to 200 ng./ml.) Histories of unusual darkening of the fingernails,
decreased interest in sex, skin rash or dermatitis, and of heart attack, were also

associated with increasing L-PCB level at borderline significance levels. 24)



.. -

Pg. 22

.. 

 

 

 

 

 

 

83'3d -
1
(aanutauoo)

. 3133366!
oroo'o sva'ot o'oz ss/tt 5'5 zvr/L 1?55
Attensnun?
sa?i'
5550'0 552'5 L'zs 55/5: 9'55 zvr/zs Entuznq ac.~

. ..-- I 
L5z5'o L55'o 5'55 55/5: L's: zvt/55 35359595
zst'o - s't 55/1 o'o 391/0 Bu::u5554?'
ssaupapa?qr
vovr'o 9'5: 55/51 5'51 sz/Iz -35511 5'
LLzs'o a't 55/1 art/z 5U5nrmon VI
5555's zoo'o 5'51 55/5 a'vt teen 
I .
qaeazq 
. ssaunzo 
5555'0 soo'o 5'0: 55/9 9'01 pauretdxa -
'uap5l: 
. . asaqa aq: 
zzoz'o Lzs't 5'51 55/5 5'5 zvt/vr ssauaq?t'a 
i i pauretdxaqn
'uappns 
I 0
ztvs'o . 1'5 55/5 5'5 zvt/zt .SuIzaaun
can't 5'05 ss?ct 5'5: art/95 Entu?no:
ZR :uaazaa' nogazodqza nuaazag uogzzodoza
oozz on: 
radar Baa-n 13591 535-1 1
muses mazes

:uwra Eugznaaegnum

1233133313

age?q unias ?q panurnqag sasuodsau moadu?s

6 

 

 

 

.TIBLE 9 (oortinued) 

 

Serum Serum . ?1 1
L-PCB level level 
4 200 2200 

Proportion Percent Proportion Percent 12 

 

 

 

 

?asting or 
repeated 3/142 2.1 2/55 3.6 0.4292
diarrhea -

 

sting or
epeated 6/142 . 4.2 4/55 .7.3 0.2925
nstipation 

Aeeling
ired or 
tPn?down 48/141 34.0 20/55 35.4 0.094 0.7591
Ipst of -
time
?0
. ouble 
oncentrating - 
mi 5 remembering 19/142 13.4 12/55 21.0 2.125
0L1446 i
ings .

1 PregUEntly I 
feeling 
tense and 37/142 26.1. 20/55 36.4 2.040 0.1524
irritable - -

Peeling as
tnough
exeli?s 8/142 5.6 5/55 ?9.1 0.2797
- were swollen 

- Peeling as

t?ough
. feet 16/142 11.3 5/55 9.1 0.197 0.6570
were swollen

unusual 

1 .
. darkening 1/142 4 0.7 3/55 5.5 0.0660
1; at fingernails 

 

(continuepl

Pg.24

1 .-


 

 0

F.

TABLE 9 (continued)

 

 

 

 

 

Serum Serum
L-PCB level 3-988 level
(200 21 ?00 
Proportion Percent Proportion Percent 82 9
Bloody or 
red urine 1/141 0.7 1/55 1.9 0.4815
Loss of 1
sense of 6/141 4.3 4/55 7.4 0.2962
ell
peereesed
interest 5/142 3.5 6/55 10.9 0.0517
in sex 
thritis .
or pain 56/142 39.4 19755 34.6 0.402 0.5259
in joints 
eak muscles 5/140 3.6 2/55 3.6 0.6354
,nusual
dark
gatohes 1
of skin 2/142 1.4 6/55 10.9 0.0066
nexplained 
tlingling 14/142 9.9 10/55 19.2 2.557 0.1091
in hands
0 explained .
loss or
diminished
anse of 2/142 1.4 1(55 1.9 0.6277
touch
Ppins I
shooting
6: 14/142 9.9 7/55 12.7 0.342 0.5564
legs 1
Sores that 
d: not 11/142 7.9 6/54 14.8 2.233 0.1351
heal well 
(continueid) 

 

Pg.25

 

1? .
ra

I
e:


1

TABLE 9 (do?tinued)

 

i

 

 

 

Serum '?erum .
L-PCB level B-PFQ level -
(200 22?0.ppb
Proportion Percent Propo%tion Percent P.
AFne or 13/142 9.2 4/55 7.3 0.4588
pimples I -

Skin rash or 1 .2 i 
dermatitis 23/141 16.3 15/55 22.3 3.041 0.0012
1 Upexpleined .
itching 17/141 12.1 5/55 10.9 0.050 0.8226
{?equent 
Idominal 11/141 7.0 4/55 7.3 0.016 0.900
Pain 1 --

weight 6/142 4.2 0/55 -0.0 . 0.0969

f.




gl?ofs-

fisher's Exact Test

 

 

I
- .


Pg.26

?.qu 4.4. .





I 4"
.

 

 

United Sum - - - 
Environmul Prcagclion? .- . -.
NOW . 198.7
. i 1 
Research and
Development 
DRINKING HATER CRITERIA DOCUMENT FOR
BIPHEHYLS (PCBS) -
Prepared for .
a - a a
OFFICE or DRINKING HATER I . ., .

Prepared by

Environmental Criteria? and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Pr?ptection?Agency
Cincinnati. OH 45268 .



 





Pg. 27
. I


.251"; ?3-3-5 



Human exposure to PCBs may come from: contact. with industrial

i
products, accidental contamination of foodstuffs or i from association with

contaminated environmental components. Similar signs of toxicity are associated

 

with oral, inhalation or dermal exposure. Chloracne is the most commonly
encountered dermatologic The lesions cause follicular keratosis with
comedone formation and acneform eruptions. Other reported dermatologic 
include rash, burning sensation, pigmentation (darkening), thickening, and discoloration
of the fingernails. Hepatic effects associated with PCB exposure include
hepatomegaly, hepatic enzyme induction wjith accelerated rate of drug metabolism,
and hepatic dysfunction indicated by an incirease in serum hepatic enzyme activities.
A decrease in pulmonary function (forced vital capacity), cough, wheezing, tightness

in chest, and upper respiratory or irritation were also reported in capacitor

manufacturing workers.

Two separate groups of high-risk subpopulations for exposure to PCBs
may be identified. The first group includes those persons with the potential for
frequent or high exposure, namely, occupationally-exposed workers and breast-fed
infants, as PCBs are excreted in the. breast milk of lactating humans. The second'

group includes those individuals with a limited ability to metabolize and excrete

I
PCBs, such as fetuses and neonates (2-3 months old).

i
I

Infants born to women exposed to PCB during pregnancy (Yusho incident)
were generally small for gestational age and exhibited dark brown pigmentation
on the skin and mucous membranes, gingigal hyperplasia, early eruption of teeth,
and facial edema. The PCDF impurities may also determine the severity of these

effects. (pp. 1?9, 1-10)

i
Pg.28

Risks Prom PCBs
.
M. Clark, 

Toxic Materials Branch

U. S. Environmental Pr:otection Agency, Region 

November 10, 1983

Since 1980, the U. S. EnvironmentalProtection Agency (EPA) has considered PCBs
to be carcinogenic in addition to causing reproductive and other systemic-effects. The
determination of carcinogenicity was arrived at after detailed evaluation of the carcinogenic

studies performed on animals and some epidemiological evidence in humans exposed to PCBs.

 

Previously, in 1978, the International Agency for Research on Cancer, a highly prestigous
organization of world experts on cancer, concluded that PCBs were an animal carcinogen.-
In October, 1980, EPA published an ambient uirater quality criteria for The carcino-
genic risk assessments were performed by Carcinogen Assessment Group which?was

made up of scientists from EPA, the Food and Drug Administration, and the National
. I - .
Institute for Safety and Health (NIOSH). The 'ambient water quality criteria document


contains the following statement: 

For the maximum protection of human health from the potential
carcinogenic effects due to exposure of biphenyls
through ingestion of contaminated!water and contaminated aquatic
organisms, the ambient water concentration should be zero based
on the non-threshold assumption fo?lr this chemical. However, zero
level may not be attainable at the present time. Therefore, the
levels which may result in incremental increase. of cancer risk

over the lifetime are estimated at r10'5, 10's, and 10?7. The
corresponding recommended criteria are 0.79 ng/l, 0.079 ng/l-

and 0.0079 ng/l, respectively. If the above estimates are made for
consumption of aquatic organisms only, excluding consumption cf
water, the levels are 0.79 ng/l, 0.079 ng/l, and 0.0079 ng/l,
respectively. vii).

It should be noted that ng/l (nanograins per liter) values indicated represent PCB
concentration in the parts per trillion range or one million times less than parts per million

(ppm). Therefore, EPA has determined that PCB concentrations should be extremely low or

 

non-existent and that humans should receive thle most minimal exposures to PCBs to keep'
the risk of cancer within acceptable limits.

i
Pg. 29

I
I
I
1
I

More recently (August, 1982) EPA reaffirmed the previous position onthe carcinogenic
effects of PCBs. EPA's Health and Environmental Review Ditlfision, in response to comments

submitted by the Chemical Manufacturing Association and the Edison Institute, cited new,

 

further evidence on carcinogenic effects in workersexposed to Three epidemio-
logical studies cited, Zack and Musch (1979), Brown and Jones (1981) and Bertazzi, et al (1981)
all reported increase cancer deaths (primarily liver and lung cancer) among workers exposed
to PCBs. Since EPA has determined that there exists no safe level for P035, because of
potential carcinogenic effects, the work place environment must be as free from exposure

to PCBs as practically possible. This conclusilon is supported by the following excerpts from

1977 criteria document for 

Based on the findings of adverse reproductive effects, on

its conclusion that PCBs are potential carcinogens in humans 1
and on its conclusion that occupational and animal studies have 1
not demonstrated a level of exposure that will not subject the

worker to possible liver 1njury, NIOSH recommends that the TWA
concentrations of 1n the breathing zone of workers be main-

tained at or below the minimally detectable TWA concentration

for up to a 10-hour workday, 40-hour work-week. NIOSH considers

the minimally detectable concentration of PCBs for the monitoring

of occupational exposures to be 1 u'g/cu 111, based on its review of
the literature and the methodology! presented in Appendices I and 11.
(Pg. 157).

It is recognized that employees handling PCBs may have skin
contact with these substances, potentially resulting 1n dermato-

logic and systemic effects. Consequently, appropriate work practices,

training programs, and other measu'res should be required, regardless
of the concentrations of airborne PCBs. Therefore, occupational
exposure to PCBs has been defined as working with P035 or with
equipment containing PCBs that can become airborne or that' can
spill or splash on the skin or into the eyes, or the handling of any
solid products that may result 1n exposure to PCBs by skin contact
or by inhalatiOn. (pg. 157) I

It should be pointed out that the recommended TWA (time weighted average) of 1 ug/cu 
referred to corresponds to an air concentrationof PCB's in the low parts per billion.
Based upon the arguments presented above it is clear that it cannot be scientifically

argued that PCB concentrations of 50 or less constitute a safe level to which humans

can be exposed. Although a practical cutoff point for disposal of P035 or cleanup must Iexist

Pg. 30
-2-

References

there should be careful consideration given iT those circumstances where exposure to PCBs
could occur. Therefore, whenever possible, any exposure to PCBs should be prevented
including the potential for exposure, and all spills, particularly those in the work place
environment must be cleaned up to the extent possible to protect individuals from the

risk of cancer or other potential health effects.

1. U. S. Environmental Protection Agency, "Ambient Water Quality for 
Biphenyls," October, 1980.

 

2. U. S. Environmental Protection Agency, ?Response to Comments on Health Effects of
PCBs Submitted by the Chemical Manufacturers Association and the Edison Electric
Institute, August 18, 1982.

3. National Institute for Safety and Health, U. S. Department of Health, Education and
Welfare, "Occupational Exposure to Biphenyls September, 1977.



1
Pg. 31

 





4,1

.3



?1-2 7 3*

PCBs be odorless and tasteless.
Acute effects are minimal.
Inhalation of concentrated vapors containing PCBs can cause irritation to the nasal passages
and sometimes violent headaches.
Tolerance Level Industrial Handli_ng
Approximately 1 mg per cu. meter of air.

If ingested or inhaled industrial use PCBs can: produce moderate to severe effects.

Chronic exposure

 

Can cause chlorachne, to. hepatic coma, and death. If exposed additionally to carbon
tectrachloride the toxicity, especially in the liver, is intensified. PCBs induce degradation"

of estradial to estrogen (thus) inhibiting the blody's capability of metabolizing calcium (calcium
metalolism) 3
PCBs depress hemoglobin. MMFO is effected;-? enzymes that hydrolize a large number of

drugs and steroids.
I

There are four variations in the effects 1
(1) Latent (2) Viseceral (3) Manifest (1i) Tardive
LATENT

There are no but PGBs can be found in tissues, and can be transferred to the fetus

or to a nursing baby through the mother's?breagt milk. The babies born of mothers contaminated
with PCBs will show dark pigmentation of the inails, mucous membrane of eyes and mouth.
VISCERAL

No dermatological signs, but victims will experience fatigue, nausea, vomiting, mild jaundice
and colic?like abdominal pains. Some can experience diarrhea, cough, chronic bronchitis,
asthmatic attacks, and pneumonia. PCBs can be found in the sputum, blood or tissue. In

some instances, there is increased serum triglyceride level of the B-11 poprotien.

MANIFEST

Dermatological signs are present, which include chloracne, a skin or follicular eruptions

I
which cause dark brown pigmentation of the skin, nails and mucous membrane and discharge

ng. 32


a



.1

I
i

I
from the eyes. Loss of hair, loss of libido, fatigue, numbness ?of extremities, headaches,

abdominal pain, nausea, dizziness.

Long-range - Higher neural disturbances, i.e.

 

disturbance in lipid digestion and metabolism


1

memory loss, local impairment of circulation, 

bone and joint deformities, morphological

changes in teeth of adults, and poor teeth development in children.

TA RDIVE

Delayed - up to three years before

are expressed

 

Salvatore R. DiNari
and Anne Marie Des Marias

University of Mass.
Amherst, MA 01002
Chem. Vol









I


5:3.

Most common associated with adverse health effects due to PCB exposure are:


Contact dermatitis: Chloracne, skin rashes, itching
Eye-irritation-burning,
Burning nose, face, dry throat, nausea, dizziness, headaches.

Prolong exposure can result in liver injury

 


-

Jig

.. i
that "the concept of a threshold exposure level has no practical significance where carcinogens

are concerned" (EDF v. EPA, 510 F. 2d 1292, D..C. Cir. 1975). 5

Conclusion

In view of the above findings with respect to the extreme non-biodegradability of .- - 

man?s inability toccompletely excrete PCBs, the inability of researchers to establish a if;

 

dosage of PCBs, the fact that PCBs are carcinogenic in animals and suspected carcinogens in
humans, and their ability to greatly bioaccumulate, the Administrator of the Environmental

ProteCtion Agency has determined that there is no level of exposure of human beings or' the

environment to PCBs which is insignificant.

The TSCA specified that after January 1, $978, no person may manufacture, process, 

distribute in commerce, or use PCBs in other than a totally enclosed manner 
Totally enclosed manner is defined by TSCA to mean a manner which will ensure no significant

exposure of humanbeings or the environment to; PCBs, as determined by EPA by rule 

Therefore, as a consequence of the Administrator?s finding, under the TSCA, subsequent
to January 1, 1978, no person may manufacture; process, or. distribute in commerce or use any
PCB in any manner which will release any detectable amount of PCBs to the environment
unless the Administrator authorizes such activity by Specific rule.

 

 

- 1.
guru?m. 





 



Significance of Exposure to PCEs
PCBs have been demonstrated unequivocally to induce a variety of adverse effects
on. the health of humans and experimental mammals. These effects have been documented
fully in Criteria Documents prepared by this Agency ("Criteria Document for EPA

Report o. 440/9-76-021, July 1976), by the National Institute for Occupational Safety and

 

Health ("Criteria Document: Recommendations for an Occupational Exposure Standard for

Biphenyls", 1977 draft report) and by the World Health Organization

.(Environmental Health Criteria for Biphenyls and Terphenyls",

1977 draft report). Further, these effects have been reviewed in detail in expert testimony at
a public hearing before this Agency and have {been accepted in full in a prior decision by the
Administrator ("Toxic Pollutant Ef?uent Standards?Standards for Biphenyls

Final Decision", 42 F. R. 6532-6556, February 2, 1977). '1

i
Consequences of Exposure to PCBs 
PCBs are absorbed through the lungs, thie gastrointestinal tract, the intact skinhand
(in experimentally exposed animals) the eyes.: After absorption PCBs are circulated through-
out the body in the blood and are stored in a variety of organs, especially in adipose tissue
and in the liver, adrenal glands, and skin. Regardless of the mode of administration, PCBs
can be absorbed into the body and distributed via the blood at sufficiently high concentra-
tions to produce pathological changes in the liver, kidneys, reproductive organs, and parts
of the endocrine and immune systems.
The toxicity of PCBs in mammals is not lstriking for its immediate or acute effects,
but rather for its chronic effects which, are manifested only after prolonged (not necessarily
continuous) exposure to low levels of 2035. Many of the toxic effects of PCBs in mammals
have been reported at extremely low levels of exposure, in several species at dietary levels
of only 1-2.5 partsper million (ppm) or even less. With one possible exception, "no-effect"

levels of exposure to PCBs have not been established for any experimental mammal: reports

of "no-effect" levels have been based on studies involving short periods of exposure, incomplete

. Pg. 37


 



 



e3

 

-

.
toxicological evaluations, or both. For example, 0.1 mg/kg/day (equivalent to about 0.8 

in the diet) has been reported as a "no-effec level for the induction of liver enzymes in
rats, but in another-experiment marked effects were reported after exposure of rats to

0.5 for only 21 days (see 42 ER. 6537 for a full analysis of reported toxic effects at

low exposure levels).

Toxic Effects in Humans

1 Toxic effects of PCBs in humans have been reported both as a result of occupational

 

exposures (primarily to PCB vapors) and in the general population as a_ result of an incident
(known as "Yusho") in Japan in 1968, in which more than 1000 persons were poisoned by
inges?Ltion of cooking oil contaminated with P035 and with dibenzofurans
The outstanding signs of poisoning by both routes are skin eruptions (a condition
known as "chloracne") and discharges (hypersecretion of the Meibomian glands of the
eyelids). These effects are most conspicuouslbecause of the immediate discomfort and
disfigurati'on which they produce. Hyperpigmentation of the skin, nails, and mucous mem-
branei'ls, swelling of the upper eyelids, and congestion of the eyes are also of frequent
occurrence. Digestive disturbance, jaundice, {and impotence have also been reported in
workers exposed to In other studies, workers have complained of dry or sore throat,
skin rash, gastrointestinal disturbance, irritation, and headache. Japanese victims of
Yusho: continued to suffer from of internal disorders, .such as fatigue, abdominal
pain, disorders of the peripheral nervous systelm, cough, and menstrual irregularity, as late
as 19754, six years after exposure.

130th occupational poisonings and Yusho have been reported as resulting from very
low leivels of exposure to PCBs. In one study, ore throat, skin rash, gastrointestinal
disturbances, and other were reported by workers exposed to PCB concentrations
of only 14-73 ug/m3 (12-60 parts per billion (ppb) 1n the air of the breathing zone). The PCB
mixtures involved included Aroclors 1016 and 1242. In another study, chloracne was associated

i
with PCB concentrations in the air of the workplace of about 100 ug/m3 (30 ppb) (These and

1 13.33
1 -19- 
i

 

I


..

otheri reports in which occupational disease has been associated with measured concentrations

of PQBs in the air or in the blood of the affe ted workers-are summarized in the NIOSH draft

Critei'ia Document, pp. 49-64). In the case of Yusho, the minimum dose of PCBs associated

with overt was estimated to be about 500 mg, ingested by a 50 kg person over

about 100 days about 100 ug/kg/day).
The possible role of in the human poisonings summarized above is difficult to

determine. Although the Japanese PCBs responsible for the Yusho incidentwere unusually

contaminated with the similarity of the Yusho to those, of chloracne

 

induced by industrial-grade PCBs indicates that the latter are responsible for much, if not
most, of the observed toxic effects. All comniiercial PCB mixtures (including Aroclor'1016)
have been reported to: contain trace quantities of (see NIOSH draft Criteria Document,
Table Hence it is impossible to disentangle completely the toxic effects of PCBs from
those of and-it is necessary to regulate the commercial mixtures with recognition

that part of their toxicity may be attributable to these unavoidable co-constituents (see 42
F.R. 6543).

There is suggestive evidence that PCBs (alone Or in combination with may
cause cancer in. humans. A preliminary tabulation of deaths amongst Yusho victims through
1975 suggested an excess of cancer of the liver and stomach. A preliminary study of 92
workers considered to have been exposed to PCBs at a New Jersey facility between 1941
and 1957 showed a significant excess of maligniant melanoma and pancreatic cancer. Another
study of more than 300 PCB manufacturing workers has shown an excess of lung cancer.

(See summary in NIQSH draft Criteria Document, pp. 64-66). Although these three studies
are still incomplete and are not wholly consistent with each other, they provide grounds for

additional concern about the effects of low-level chronicexposures to_PCBs.

1
Toxic Effects in Mammals I

. 1
Experimental studies of the effects of PCBs in mammals have chieflyinvolved rodents

and rhesus monkeys, but also to some extent rabbits, dogs, pigs, mink, guinea pigs, and other
Pg. 39
- 11' 

:3

94'

uni}



'1
3 .
-r




 

a

species. The advantage of experimental studies with animalsiis- that the degree of exposure
.can be COiIgltI?OIled and that exposure can be maintained for the lifetime of thebanimal. Such
studies have demonstrated pathological chanfes in various organs, most notably the liver.
They have also demonstrated effects on reproduction; embryonic, fetal, and neonatal toxicity;
teratogenic effects; effects on exposed via nursing; effects on the immune system;
effects on the endocrine. glands; and finally carcinOgenic effects after prolonged exposure.
Even 10 for 8 weeks in the diet of guinea pigs reduced the cells that produce-
antitoxins in the response to injected .tetanusl toxoid. This was reflected in decreased gamma- 
globulin levels in the blood. This concentration of PCBs produced no other demonstrable
tissue change. In another experiment 50 ppm: for only 3 weeks in the diet supressed immunity
and caused severe liver damage and reduction in the size of the thymus gland. This effect on
the thymus has been reported in several other: species exposed to PCBs and indicates an
effect on another part of the immune system.
The toxicity of P085 to rhesus monkeys. has been demonstrated in several studies.
In one study monkeys were killed by prolonged exposure to Aroclor 1242 at all concentra-
tions down to 3 in the diet, the lowest level tested. In another series of studies, .female
rhesus monkeys fed Aroclor 1248 at 5 and 2.5 in the diet suffered severe reproductive
dysfunctions. Only 5 of 8 monkeys exposed to the lowest dose level gave birth, and their

infants were extremely small. Two of 'the live-born infants died within four months after

'birth and the surviving animals have shown impaired behavior and learning capability. Rhesus

monkeys are believed to be the best animal model for the toxicity of PCBs in humans, because

the of PCB toxicity in monkeys Closely resemble those of chloracne and Yusho

(42 ER. 6535, 6537).

Carcinogenic, teratogenic, and mutagenic effelcts
PCBs have been shown to be carcinogenic in rats and mice in a number of experiments
(see summary in 42 In one carefully-conducted experiment, lifetime exposure of

1
rats to Aroclor 1260 at 100 in the diet ca sed a high incidence of carcinomas (26/184)

Pg. 4o
.. 12 -

h?mv-?l

 


..
.

i
1

and neoplastic nodules (144/184) in the livers of exposed rats? In another experimenti rats 
were exposed to Aroclors 1242, 1254, and 12 0 for 24 monthle' Rats exposed to all three
mixtures at 100 in the diet- deveIOped liver tumors at fairly high frequency; pathological
changes that are probably pre-cancerous were reported in rats exposed to only 10 

(42F.R. 6538).

Recent studies have shown that PCBs are also teratogenic and mutagenic. Beagle dogs

 

exposed to Aroclor 1254 at. and 5 mg/kg/day during pregnancy suffered impairment of
reproduction and there was a high incidence of patent fontanelles in the surviving 
More serious effects were reported in pigs, in which exposure to 1 mg/kg/day during pregnancy
caused an increase in fetal resorptions; exposure to higher doses lowered fertility further and

caused a variety of defects 1n the (text illegible at this point) fontanelles (see NIOSH



draft Criteria Document, pp. 98-99). 

and co?workers (Research Communications in Chemical Pathology and
Pharmacology, 15: 563-570, 1976) have shownI that '4-chlorobiphenyl is a potent mutagen
in the Ames test for bacterial mutagenesis. The mutagenic activity of PCBs decreased with

increasing chlorination and the more chlorinated mixtures were almost inactive.

Enzyme Induction by PCBs and their Metabolic Activation

PCBs stimulate the induction of enzymes by liver cells. These enzymes oxidize PCBs
of low chlorine content to water soluble comptunds- that can subsequently be eliminated
through the urine or feces provided that a chlorine atom does not occupy the point of attack
by the enzymes. The remaining or unattacked PCBs concentrate in various fat?containing
tissues such as brain, thymus, adrenal cortex, liver, andfat depots. The major oxidant
induced by Aroclor 1016 is cytochrome P-450 i both rats and humans. This cytochrome is
involved in the oxidation of many important drugs used in medical practice and would, therefore,
interfere with treating diseases in humans. This view is supported by a study in workers
exposed to Aroclor 1016. They were administered a drug whose half-life is a measure of
activity. The half life was about 2/3 that observed in controls, establishing that  such

.41
-13- 

?a



drugs are more rapidly metabolized in PCB ,osed workers. 1Aroclor 1016 also induced
1
.
benzo(a)pyrene hydroxylase activity, although to a much lesser extent. This is an enzyme

that is thought to be significant in converting certain chemical compounds into active
carcinogens. Aroclor 1254 is also a potent inducer of cytochrome P-448 in liver microcomes,
which enhances the activation of carcinogenic compounds. Nevertheless, Aroclor 1016 increased
hydroxylase activity by 5096. The workers had 'shown no clinical manifestation of PCB toxicity.
(A.P. Alvares, A. Fichbein, R. B. Anderson, and A. Kappas. Alteration in Drug Metabolism

in Workers Exposed to PCBs. Clinical Pharmacology and Therapeutics, Vol. 22, pp. 140-146,
197 7.) 

A number of studies have shown that PQBs are metabolized by oxidizing enzymes in
the liver to biologically active and potentially: hazardous metabolites. Particularly significant
studies have been carried out with - tietrachlorobiphenyl, which is a substantial
component of the major commercial PCB mixtures, including Aroclors 1016, 1242, and 1254.
Several studies have shown that this component is metabolized via reactive intermediates
(arene oxides and dihydrodiols) which are bound to macromolecules within cells and are

implicated as causative agents in toxic, carcinogenic, and mutagenic effects (42 -F.R. 46533,
6542).

 

.Pg. 42

 



 

I

Letter, December 29, 1987, from John A. Moore, Assistant Administrator far Pesticides
and Toxic, Substances, United States Environmental Protection Agency, Washington, 


i
i 

1

 

Based on all the information (animal, human and various other studies). the Agency
concludes that PCB's are probable human carcinogens. 1)



 

 

53.1.:

Pg. 43

 

REVIEW OF HUMAN HEALTH AND CARCINOGENIC
RISK POTENTIAL 

Submitted in mum]? of the Terms of
for the Special Panel {on Occupational Risk of
Mortality from Canccr from Exposm-c to 

August 10. 1987

Williaml. Nichdson. 
Division of EnVironmml and gowpa?onal Medicine
Mount Sinai School 9f Medicine
New Yak. Newi York

 

Pg. 44





L..-

 

i


in.


 

ACKNOWLEDGEMENTS

I

The contributions of Pier Banzai. David Brown and For who

performed additional analyses on the data for ?their cohorts and supplied

supplementary information for inclusion in this report. are gratefully acknowledged.

 

Pg. 45

 

 


.

i


Summary 

A review or "meta-analysis" has been conducted of?all the available data relating
to the cancer mortality risk of workers exposed to PCBs during the manufacturing of
electrical capacitors. This analysis was performed with the cooperation of all researchers

who undertook the initial studies, each of hom provided data and analyses for this review.

 

This cooperation was of particular importance as it allowed data from different studies
and different nations to be combined according to time and exposure variables of importance
for identifying a potential PCB effect. These time and exposure variables of importance
were identified from models of the age, itime and exposure dependence of cancer from

I
exogenous agents and from experimental data on cancer risk. I

The results of the analysis provide strong evidence that PCBs produce cfancer of
the liver, biliary tract and gallbladder in] humans. While only seven such deatlhs were
identified in all studies, the high and statistically significant SMR, 275, is strengthened
by the concordance of animal data, results of . human exposure to chemically. similar
compounds and the observation of an appropriate time and exposure relationsijiip with
cancer risks. The review also suggests an increased risk of cancer of the and
hematopoietic system. Here, however, the overall evidence is less strong andlfurther
data are required before a definitive statement can be made on causality.- Cancers of
the rectum, kidney and urinary bladder were also elevated in the combined analysis.
However, the numbers of malignancies at thiese sites were too few to allow any statement

to be made on a relationship with PCB exposure. 45)

 

Pg. 46

 


?my 5%

s92 

UNITED STATES ENVIRONMENTAL PROTECTION AGENM 

an; 

 

WASHINGTON. on. 20450 .
no? 
ALB 2 IQBT
owner or
AND roam: sunraucu
MEMORANDUM

SUBJECT: Comparison Of Animal-Based Expected and Human Observed
Risks Associated with PCB Exposure

.c . 
PROM: Cheryl Siegel Scott. Bpidemiologis - 
Design and Development Branch 
T0: Denise Keehner, Chief -
Chemical Regulation Branch

?31?

THRU: Fundy R. Stroup. 
Design and Development Branch




izes my comparison of the expected
uman cancer risk for PCB and
epidemiologic studies Tou
nce Dick Hill questioned the validity
that are based on the estimate of
lar request in March 1987 regarding
liver cancer riSk in the Yusho-
exposed population. I refer you to the enclosed March, 38. 1987,
memorandum to Dick Hill. This current analysis is more
comprehensive than that performed in March in that I identified
two other recently released cohort mortality studies which
reported statistically significant increases in either liver or
gastrointestinal cancer in PCB-exposed. The estimate Of lifetime
excess cancer risks to PCB based on.1iver tumors in the Norback
and Weltman (1985) rat carcinogenicity study fall in between
those estimates which were Observed En the three epidemiologic 
studies. The estimates of for one study of 0.8. capacitor
workers was lower by approximately an order of magnitude than
P(d)a, whereas, the estimate of P(d1h for Italian capacitor
workers was very near the expected P?d1a. The for the
study of Yusho exposed was an order of magnitude larger than
P(d)a. Although exposure characterisation limits the accuracy of
this analysis, liver cancer risks observed in these three cohort
or follow-up mortality studies corroborate the animal-based
estimate Of lifetime excess cancer risk for PCB mixtures.

This memorandum summer
animal-based estimates Of 
those risks observed in the
requested this comparison si
Of the estimated excess risk
q1*- Dick Hill posed a simi
an observed elevatiOn in the

Au; 28 '98? Pg. 47



IARC has recently reclassified the epidemiologic evidence on
PCB from ?inadequate" to ?limited", however. the human data is
not sufficient for quantitating low-exposure human cancer risks.-
In light of less than sufficient epidemiologic data for risk
modeling. we must rely on animal-based estimates for predicting
the upper limit of human cancer risks associated with low-level
exposures. The validity of the animal-based estimate of excess

with. Although modeling of the epidemiologic data cannot be
done, we can make comparisons between the lifetime excess cancer
risk estimates from the human evidence and those based on liver
cancers in animals. Such analyses have been performed, or ones
based on similar assumptions, for asbestos, formaldehyde.
methylene chloride, and gasoline.

For this analysis, I identified three studies from the draft
OHEA document on PCB's and from a references list from IARC's
March 1987 Working Group on PCB's (attached to end of
memorandum). These studies were the only ones which I considered

three identified studies are that of Amano gt (1983) who
studied mortality patterns among Yusho exposed individuals,
Brown (1987) of NIOSH who studied mortality among electrical
capacitor manufacturing workers. and Bertazzi et a1. (1987) who

F.

studies mortality in Italian capacitor manufacturing workers.

All studies report an excess of liver or gastrointestinal
cancer mortality among PCB-exposed when national rates are used
as the comparison. Amano et 21? (1984) observed for liver cancer
a sun of 498 base?d on 3 deaths. As 1 identified in my
March 38, 1984, memorandum, the is seeking further
information on the Yusho-exposed cohort, however, to date. they
have not received any new data. Brown (1987) observed a SHR of
263 based on 5 deaths for liver cancer. Four of these
5 deaths in the Brown study occurred among women in one of the
two plants, resulting in a SHR of 444 Bertazzi st 21'
(1987) observed for gastrointestinal cancer a sun of 346
based on 6 deaths. One of the six deaths was from
liver cancer.

Two components are integral in this analysis, the
'calculation of P(d)h and the calculation of the LAD. In the
first component. the SHR is reexpressed as the relative risk
(RR). from which the excess risk (ER) is derived.

(1) SMR 0.ER.
Since the excess cancer risk over background is the important
parameter, something needs to be known about the background

cancer rate. A good estimate of the background lifetime risk of
cancer is the proportion of site-specific deaths to total deaths pg,43

(Liu, Winbush, and Springer, 1989).

(3) Background lifetime risk Number of site-specific
deaths per year/Number of total yearly deaths.

Given these parameters, an estimate of the lifetime excess cancer
risk can be obtained from the following formula.

(4) P(d)h - ER Background lifetime risk.

The second component of this analysis is the calculation of
the exposure estimate, the lifetime average dose (LAD). expressed
on a mg/kg/day basis. The use of this LAD assumes a constant and
chronic exposure over the person's lifetime. The limitations of
this averaging procedure are described elsewhere. For in this_

The animal-based expected lifetime excess in cancer risk for
the human studies is derived from the g1* and the LAD.

(5) P(d)a q1* . LAD

For this analysis, 7.7 is taken as the value for
91 

Appendix A contains for the Amano ?3 21., Bertazzi ?5 31.
and Brown studies the estimates of the RR, ER, LAD, P(d)h, and
P(d)a. Figure 1 depicts the relationship between P(d)h and
Ptd)a. As seen from Appendix A. the observed estimates of P(d)h
based on the Brown (1987) data are about an order of magnitude
lower than the expected for that study. 5.13-3 
versus 6.35-2 The estimate of P(d)h, 1.88-1, for
Bertazzi 35 a1. (1987) is very close to the expected estimate of
P(d)a. 2.4E-IT if the midpoint of identified exposure levels from
1954 and 1977 is used as the LAD. The observed estimate of P(d)h
based on the Amano et 51. (1983) data [P(d)h of 1.18-1] is 11
times greater than the expected estimate of P(d)a, 1.88-2. Thus,
the animal-based estimate of human cancer risk falls somewhere in
between the lifetime excess cancer risks observed in the
epidemiologic studies.

Several uncertainties exist in this analysis which may
account for the divergence between the human-based estimates of
P(d)h and those predicted using liver tumors in the rat study.
P(d)a. First, the exposure estimates calculated for the three
studies may not be precise nor accurate. Brown (1987) identified
in Brown and Jones (1981) a range of exposure levels for Arochlor
1016 obtained during a NIOSH walk-through. Brown and Jones
(1981), however, stated past exposures were higher and, that
before 1971, other Arochlors, particularly Arochlors 1242 and
1254, had been used. Bertazzi st 51. (1987) identified exposures



Pg.49

3919. The above information is particularly pertinent since the

Second, this analysis does not take into account the
different toxicities in PCB isomers. Rats were exposed to
Arochlor 1269 whereas. human had exposures to Kanechlor 499, and
Arochlors 1916, 1242, and 1254. A crude comparison of the 
for hrochlor 1269, 1242, and 1254 shows that Arochlor 1269 is
less toxic than the other two Arochlors. I could not find data
on the acute toxicity of Arochlor 1916. The general consensus,
however, is that there is no consistent relationship between
formulation and reported 

Third, this analysis does not take into account different
routes of exposure, and thus different target tissue
concentrations. The animal carcinogenicity study exposed rats
via the diet, the same exposure route for the Yusho-exposed
cohort. The capacitor workers studied by Brown (1987) and by
Bertazzi gt a1. (1987) were most likely exposed via dermal
contact and inhalation. In fact. the atmospheric monitoring
levels reported by the authors may not be an accurate surrogate
for the worker's exposure. Although not exactly related,
Bertazzi 35 a1. examined PCB workplace surface levels and those
levels found?3n workers hands. Bertazzi ?3 51. found a much
narrower range and lower PCB levels on workers hands than on
workplace surfaces. The toxicokinetics of PCB are similar for
all routes of exposure, however. I could find very little written
on body burden accumulation other than blood levels. A group of
U.S. capacitor workers were reported as having PCB blood levels
some 59 times higher than a group of Yusho-exposed patients
(Erikson, 1986). Blood levels reported for Italian capacitor
workers were similiar to those reported for U.S. capacitor
workers. Whether these blood concentrations are representative
of all members of the two cohorts is unknown.

One needs to ask how the above limitations influence the
estimates of Ptd)a and Ptd)h. If past exposures in the Brown
cohort were to higher levels of possibly more toxic PCB's, then
one might expect the estimate of P(d)h to be higher than P(d)a.
This observation may lend support to the argument that the
-animal-based estimate of lifetime excess human cancer risk may be
too high. Several alternative factors, however. may explain the
difference in expected verses observed estimates of These
are: differences in absorption between routes of exposure, the

The higher estimate of P(d)h from Amano gt 31. as compared
to the expected Ptd)a is not unexpected given the difference in

toxicities between Kenechlor 499, the major contaminant of Yusho~pg.50

oil, and Arochlor 1266, the rat exposure. Kanechlor 4GB is
acutely more toxic (L059 of 1.3 ml/kg) than Arochlor 1260 (L059
of 6.3 ml/kg) by a factor of 4.8, close to the difference in the
estimates of P(d)h and P(d)a for Amano gt (1983). Evidence
supports the theory that PCB's were not solely responsible for
the observed acute effects. A comparison of chemical
constituents of these two compounds show Kanechlor 400 contains
roughly 18 PCDF's dibenzofurans) (Morita st
51.. 1977) whereas Yusho oil contained approximately 5.0 
PCDF's (Hagayama st 51.. 1976). Yusho oil, in addition.
contained quateryphenyls I could not
find at what level Kanechlor 49% contained these compounds.

If the differences in and FCC levels between Kanechlor
400 and Yusho oil contribute for the observed increased risk in
P(d)h over expected, P(d)a, then little can be gleaned regarding
the validity of the animal-based PCB risk estimate since at this
time, the complete characterization of the toxic components has
yet been ascertained.

In summary, a comparison of the lifetime excess cancer risk
observed in three epidemiologic studies. P(d)h. to that expected
based on animal data, P(d)a, shows the Ptd)a are encompassed by
the estimates of Ptd)h. Limitations in the exposure
characterization in the three epidemiologic studies and in the
toxic potential of PCB chemical mixtures other than that tested
in animals introduce uncertainty into this comparison. When
assessed on a macro level, however. this analysis shows the
observed human liver or gastrointestinal cancer risks for PCB
corroborate those expected based on liver cancer in rats.

Enclosure
cc: Elizabeth H. Margosches

Cindy Stroup
Martin P. Helper

Pg.51

 

i arm

WW :53;

?33% Research aria - "ea-"w
Deveiopmem ., -

 

DRINKING WATER DOCUMENT FOR
POLYOHLORINATED BIPHEHYLS (P035)

 

Prepared for

?fi?lCE ?ll-111% HATER

Pr??ared by .

Emit-0mm! Criteria and
Amt! (?rm
Cincinne? 0545268

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m:ueurcmoamn

WITE

This damn: ie I gre?nieery sun. It has not teen family released
by the II. 5. Environment Pretectiee Agency and mu no: at this stage Ie

construed ter represent my yeiicy. It is being circeleieu tor cements
en in techice'l eccerecyd ge'licy. in?ections.

-mnom1 Karma
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Pg. 52

 

-

 



 


Summary 

'Nine mechanisms (enzyme induction, inhibition of mitochondrial
respiration, estrogenic effects and altered steroid metabolism, mobilization and

redistribution of stored PCBs, covalent binding to cellular macromolecules, altered

calcium metabolism, immune suppressionll decreased thyroglobulin proteolysis, and

 

metabolism) have been implicated in the induction of toxic effects by PCBs. Enzyme
induction has been demonstrated in a wide variety of species. The enzymes induced-
by PCBs may be typified as either type or phenobarbital
type (P-450). Minimum structural requirements for P-450 induction are symmetrical
substitution at the ortho and para positions. induction requires substitution
at the para and meta, but not ortho, positions (Goldstein et al., 1977). The induction
of P-448 appears to correlate with the lontherm toxicity of PCBs within a particular

species (Yoshimura- et al., 1979), but this correlation does not extend to interspecies

comparisons (Shull et al., 1982).
i
PCBs may either inhibit or ulncouple mitochondrial respiration. There
is some evidence that the dominant effect depends on both the degree of chlorination
and the concentration of PCB (Sivalingan;et al., 1973; Khan and Cutkomp. 1982),


but the mechanisms involved have not been elucidated.

PCBs have a number of effects on reproduction. These effects may
result from a direct estrogenic effect of PCBs or from altered metabolism of steroid
hormones secondary to enzyme induction. Bitman and Cecil (1970) have found that
PCBs with (5496 chlorination have weak estrogenic activity. PCB treatment has
also been demonstrated to induce the metabolism and lower the metabolism !of

progesterone, estradiol?17, and testosterone (Orberg and lngvast, 1977; Derr and

02390 VII-11 03/14/94

I

Pg. 53

u.


 

Dekker, 1979; Conney et a1., 1967; Kintzm:

PCBs are highly lipophilic 
for long periods of time. During periods

as starvation, these stored PCBs may be

in et al., 1977).

:ompounds that may be stored in body fat
when body fat depots are mobilized, such

redistributed, resulting in a delayed toxic

effect.

 

Metabolism of PCBs may produce an electrophilic species (epoxide)
that can bind covalently to cellular macromolecules. PCBs have been observed
to bind to protein, RNA and DNA in microsomal metabolizing systems 
and Safe, 1978; Shimada and Sato, 1980),. Binding to cellular DNA may, thus, be
the mechanism by which PCBs induce theirgmutagenic and carcinogenic effects. I.



Kirkachi and Masuda (1973') observed accumulations of calcium in
the heart and kidney tissue of individuals Chronically poisoned with PCBs. One study
in rats (Yagi et a1., 1976) has also indicated the potential of PCBs to alter calcium
metabolism i_n m. .

Suppression of the immune system is one of the more sensitive indicators
of PCB intoxication. Conradt et al. demonstrated an inhibition of RNA
in macrophages exposed to Aroclor 1242. They suggested that this inhibition
may account for the immunosuppressive action of PCBs, since RNA is

suspected to be involved in the acquisition and transfer of immunity.

02390 . vn..12 08/14/84

I

 

. Pg. 54



 



.

PCB treatment produces numerous alteratitons- in the structure and
function of the thyroid gland, thus altering the homeostaitic mechanisms regulating
energy balance i_n 22?2- The exact mechanism responsible for these effects is not
known, but the effect appears to occur at the point where lysosomes fuse with colloid

droplets (Collins et al., 1977, 1980a; Collins and Casper, 1980). When this fusion

 

is bloCked, thyroglobulin cannot be proteolyzed to thyroxine and tri-iodothyronine

and collodial thyroglobulin accumulates in the follicular cells.

PCBs produce a wide variety of toxic responses, some of which appear
to be due to the parent compound and some of which are due to metabolites. Enzyme
induction is probably a function of the parent compound, since induction is greater
following exposure "to more highly chlorinated, thus more slowly metabolized, PCBs.

Cellular toxicity, estrogenic activity and carcinogenicity are more likely to be the

result of the formation of toxic metabolites.

PCBs also alter the effects of many other compounds. Many of these
effects are the result of altered metabolism caused by the enzyme inductive effects
of PCBs (Chu et al., 1977; Villeneuve et. al., 1972; Hutton et al., 197-9; Sipes et al.,
1978; Conolly et al., 1979). Other interactions are not as well understood. Cadmium
exerts an antagonistic effect on many aspects of PCB toxicity, apparently by inhibiting
the enzyme systems induced by PCBs (Suzuki, 1980; Horio et al., 1981). Dietary

ascorbic acid supplementation reduces some of the toxic effects of PCBs possibly

by inhibiting lipid peroxidation through its role as an antioxidant (Kato et al., 1981;

 

02390 VII-13 08/14/84
Pg. 55

 

14? 

02390

I




I i

Chakrabortz et al., 1978). PCBs also inhibit the growthi of transplantable tumors

(Anderson at 31., 1983; Oesterle and Deml, 1983; Pereira et 31., 1982), butrthe

mechanism of this interaction is unknown.

 

 

VII-14 08/14/84

39g. 56'

 BIPHENYLS



 

A Report on the Biochemical Basis for Toxicity

Prepared for John R. Foster

Submitted on January 14, 1988


oa91d Schalk

I
5

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Dakid Schalk



 

P957


"qu



-1

Iiritzarcocitnc:1:iLcoi1

 



The underlying basis for biphenylw 
induced illneSs has receiVed considerable attention from the
scientific community over the past fifteen years. This research.
effort has been successful in filling in the missing links in the'
molecular chains of events culzminating in PCB induced illness to
such a degree that there is now a pressing need to communicate the
discoveries made in research lacilities to a wider spectrum of
Society - the medical community, in particular.

This report is a short review a 'few selected toPics which
relate to the early stages of PCB toxicosis. It represents part

of the authors review of over 500 artic1es and documents relevant
to the subject of PCBs.

Along with the many other medical problems known to be caused
by PCB exposure, there is now solid epidemiological evidence that
PCBs are human carcinogens. IThe U. S. Environmental Protection
Agency's Office of Pesticides and Toxic Substances has discovered
statistically significant 0.'05) exceSses of death due to liver
and gastrointestinal cancer among exposed individuals - a result
consistent with the expected 'deaths predicted by studies upon
rats. The International Agency for Research on Cancer (IARC)

recently changed the classification of PCBs from "possible" to
"probable."

 

Pg. 58

 -



PCB and related compounds cause or contribute to bad health
by first interacting with the body on lthe molecular 1evel.
Molecular activity can then lead to grossachanges such as liver
enlargement, joint inflamation, nerve damage, or cancer. Research
continues to generate information conce-rning the distribution of
PCBs among various organs, tissues, and cell components; on the
varying tendencies of PCB congeners to bind to proteins involved
in the regulation of the immune and endocrine (hormone) systems,
and on the addition of oxygen or sulfur to PCBs, transforming them
into potentially toxic compounds known as PCB "metabolites.?l

 

cafE 

Just as fat accumulates on the surface of soup, or oil
separarates from water, so fat soluble chemicals in the human body
avoid the water of the bloodstream. Like paints, all natural
compounds, drugs, and pollutants can be classified according to
whether they dissolve in water or organic solvents. With rare
exceptions, chemicals which are water soluble have strong
aversions to organic solvents, and chemicals which dissolve in
organic solvents have strong aversions to water. Compounds'which.
dissolve in water are called "hydrophilic; those which dissolve
in organic solvents are called "hydrophobic."

Lipids are relatively' small hydrophobic molecules. They
include fats, oils, and waxes. Glycerides and cholesterol are
examples of lipids. PCBs are hydrophobic, so PCB molecules which
enter the body quickly find their way to fatty portions of the so
called "lipoproteins'l which circulate in the blood and transport
hydrophobic compounds accross cell membranes and into the cell
cytoplasm, into fat deposits (adipose tissue), and onto the inside
surfaces of cell membranes.

0n the molecu-lar level, the body functions largely inside the
individual cells. There are many different kinds of cells serving
many different functions. Onelthing they have in common is the
ability to convert nutrients into energy. Cells have been called
the body' 5 "little factories." The form and struct-ural integrity
of cells is maintained primarily by compounds called "glycerides."

Glycerides are long molecules which, while hydrophobic
overall, are hydrophilic at one end. Glycerides form the
membranes which enclose the flpid (cytoplasm) inside the body' 5
cells, and form a barrier keeping unwanted compounds in the blood
stream from entering cells and?interfering with life processes.
Proteins which extend from outsi ide the cell to the inside

?Pg. 59



 

(cytoplasm) are interspersed among the glycerides. These proteins
allow chemicals outside the ell to communicate with chemicals
inside the cell by attaching either endiof the proteins, or the
assist chemicals in entering or leaving :the cell. The system
which transports vitamin and thyroid hormone from the
bloodstream to the inside of 115 may be involved in transporting

PCBs into cells. It is known that PCBs have a strong affinity fors

thyroxin binding prealbumin (TBP) in the blood.?

The inside' surface of cell membranes consists of the
hydrophobic chains of glycerides; steroids such as sex hormones,
vitamin A, and cholesterol; and many other hydrophobic compounds.
Hydrophobic compounds move eas?ly around the inner surface of the
cell membrane, but rarely cro:ss it to: enter the bloodstream or
leave unassisted to enter the cytoplasm.

Many cell membranes have a network of smaller membranes
called the ?endoplasmic reticulum.? 'Fragments of this network
constitute much of the so called "microsomal fraction" of cells:
the fraction of homogenized cells which goes to the bottom of a
test tube in a high-speed Ecentrifuge. Under an electron
microscope, the reticulum can be seen to be either smooth -or
rough. One of the first manifestations of PCB exposure is an
increase in the amount of 6a "proliferation'I of) the ,smooth
endoplasmic reticulum of the liver. 'This proliferation is
believed to be associated with increased production of certain
enzymes, called "microsomal mixed function oxydases 
which reside in the endoplasmic reticulum. A

Some of the 209 individual PCB congeners are very potent"

inducers of MFO's. The most toxic PCBs are the most powerful

inducers. The abilities of PCBs to induce MFO's is directly, 
related to their abilities to bind to :mobile proteins in the ..
cytoplasnl called "Ah-receptor proteins.? Ah?receptor proteins.?

apparently transport PCBs from the cell membrane into the cell

nucleus where the Ah-receptor protein/PCB complex stimulates'the'
production of HFO's. The Ah-meceptor mobilized PCBs may do more}
than merely stimulate MFO production. Evidence that they play a 

larger role includes the fact khat same compounds which are less
toxic than PCBs are also poten? MFO inducers. .

I

c>15_ IBaacrri czcarrggeerzeezc

Each Of the 209 individual compounds known collectively 
PCBs is unique. The six PCB congeners with at least two chlorine.. 
atoms at the meta and/or para ositions of each ring (the 3, 

4, 5, and 5' positions), but none at the ortho (2, 6, or
positions, can readily assume a flat conformation which makes



!-Pg.60



- .u .

- rife? . . .. -. ..

5 I
a i


c' .
'13? 


them approximately the size and shape of the most toxic dioxins.
Compounds with only one or ltwo chlorine atoms in the' ortho
positions and chlorine atoms in at least 4 of the meta and para
positions also significantly resemble dioxins. i

oe?tno Po 

META 
p?gA POSIT 

 

These six toxic PCB congehers have a strong tendency, as do
the most potent dioxins, to Tbind to certain of' the proteins
involved in regulating the highly complex chemistry of life.?-
other PCB congeners, particularly those with at least two chlorine
atoms at the meta and/or para gositions of each ring and only 1 or
2 chlorine atoms at the ortho positions, are also biologically
active, and similar to dioxin in their modes of action. It has
been suggested that chlorine atoms in the para positions are more
important than chlorine atoms in the meta positions for
potentiating the enzyme inducing ability, and presumably the
toxicity by On the other hand, studies correlating PCB
toxicity with similarities to the thyroid hormone, thyroxin,
suggest that the meta positions are more important.?

_It is believed that chlorine atoms in the ortho positions
render PCBs less like dioxin by' making it difficult, due to

crowding by large chlorine atoms, for the two. rings of the PCB
molecule to assume a co-planar configuration. All the dioxins are

planar.
c  Po+eln+
?mm mg.

i
I
i

The modes of action of PCB congeners which do not resemble
the dioxins are not well understood. While they are not potent
acute toxins, their long term adverse effects could conceivably be
worse than those of dioxin and the dioxin- like PCB congeners.

jpg. 61

 

 

 

I



1. Safe et a1., PCBs:Structure-Funcdion Relationships and

Mechanism
(1985).

of Action, 60 Endironmental Health PerspectiVes 47


.1

2. Safe at al., Effects of Structure on Binding to the 

TCDD Receptor Protein and IHH
61 Environmental Health Persp
PCBs:Structure-Function
Action,
Poland and Glover,
Hydrocarbon Hydroxylase Acti!
Activity Relationship, 13 Mol
a1., Separation of Pure Polych
Types of Inducers on the BaSis

Chem-Biol Interact-
Biphenyls as
EnZymes:

(1981).

60 Environmnetal Health Perspectives 47
chlorinated

Induction Haloginated Biphenyls,
ectives 21 (1985). Also: Safe at
Relationships and Mechan?sm of
(1985), citing:
biphenyl Induction of Aryl
wity: a Sturdy of the Structure
Phaarmacol 924 (1977); Goldstein et
lorinated Biphenyl Isdmers Into Two
of Induction of Cytochrome P-450_or
69' (1977); and Parkinson et 

InduCers of Hepatic Hicrosomal

Structure-Activiey ,Rules, 30 Chem-Biol Intera?t 271

 

3. McKinney et-a1.,

-Structure -

Induction ?Versus Structure -

Toxicity Relationships for Biphenyls and Related

Aromatic Hydrocarbons, 60 Environ Health Perspect 57 (1985):


l.







 

l'
I



I 






Earn ?rnmezss 
Enzymes are among the proteins which the body produces to
help regulate itself at the molecular level. The function of
enzymes is to determine the rates at which chemical reactions
occur.

Some enzymes serve to speed up the rate at which the body
destroys foreign chemicals. These enzymes are often referred to
as "detoxifying" enzymes, despite the fact that they freguently
change toxic chemicals- into compounds which are even .more toxic.=L
Compounds which are destroyed Hith the help of enzymes are called-
"substrates", and the products whiCh are created in the process
are called "metabolites". The'se metabolites are often more water
soluble that the substrates, End hence more readily excreted in
the urine. The most common metabolic pathway for PCBs involves
addition of hydroxide groups (-014). Hydroxylated PCBs may be
excreted by becoming attached; to sulfate or glucuronic acid to
form a water soluble complex.lMetabolites which are not excreted
are stored in the body or further metabolized into other, possibly
more readily excreted compounds.

Foreign chemicals in the body stimulate the production;and/or
activity of detoxifying enzymes; or, as one is likely to encounter
it in the technical or "activate" detoxifying
enzyme systems. In some situations, enzymes are activated by
compounds which bind to them], so enzyme activity can increase
without the actual number of enzyme molecules increasing.

PCBs are metabolize inside cells located in various parts of
the body, but primarily located in the liver. Significant PCB
metabolism takes place in the skin,? and in the lungs. A variety
of natural compbunds are involved in the systems which oxydize
PCBs. Oxygen atoms are provided in these systems by a variety of
proteins which each have a flat, iron-containing part resembling
hemoglobin, and which are known collectively as cytochrome 450.
These complete enzyme systems are sometimes called "mixed function
oxygenase systems (MFO's). PCB exposure induces the P- -450 MFO
system,3 including a sub-system involving cytochrome P- 448 which
is thought to be involved in transforming certain chemical
compounds into carcinogens?' There is evidence that traces of
chlorinated dibenzofurans in PCB specimens contribute

{significantly to enzyme induction.B

Enzymes'may be related to PCB toxicity in several ways:

(1) By indicating that foreign chemicals are in the body,
they help document exposure to PCBs.

 

Pg. es

. . 




 

I I

(2) Prior exposure to PCBs increaSes the activities of
enzymes which transform certain chemicals into toxic metabo1ites.
For example, the anesthe-tic halothane Iis not, ,.in itself,
particularly toxic, but it is very toxic when certain enzymes are
present _at elevated levels. A woman may have been "serliously
injured by? the anesthetic haloformt as a cansequence of
occupational exposure to Animal experiments show that

vinyl chloride and fluroxene become more toxic after exposure-to

 

(3) Enzyme systems which have been induced by PCBs can
interfere with therapeutic drug treatment by ridding the body of
the drug more rapidly than anticipated by the prescribing
physician. .

 

(4) Some PCBs and PCB byproducts induce enzymes such as P-
448 moncoxygenases-which can transform PCBs and other chemicals
into reactiVe and potentially carcinogenic compounds called
"arenes oxides" or PCB epoxides react with protein,
and to some extent with genetic material by becoming attached- to
it. Reactive PCB epoxides may help account for induced liver
damage.? I

(5) PCB induced enzymes Ican destroy hormones, the body?s
molecular messengers and regulators.

(6) The. molecular events leading up to enzyme induction play
a key role in scientific research into the biochemiCal basis of
PCB toxicity. This research indicates that before some PCB
induCed enzymes can be manufactured inside the body's cells, PCBs
must be transported insideythe cell nucleus after binding to a
protein called the "Ah?receptor." Species, as well as individuals
within species, which have the most hh- -r-eceptor protein tend to be
the most sensitive to the ill effects of PCBs, dioxins, and
related compounds.? It has been found that Some people have the
Ah- -receptor but others don't.1P If this result is confirmed by
ot-her studies, then a genetic pr-edisposition to PCB poisoning may
have been found. Researchersjin the field of PCB tOxicity have
already suggested that characterizing the extent of human
pathology caused by PCBs and rela.ted compounds may require
determining not only the levels of these toxic compounds have been
in the body, but also whether or not the patient is "dioxin
receptor positive" or "dioxin receptor negative. PCDF
induction of one of the mixedlfunction oxydases, knewn as l'aryl
hydrocarbon oxydase varies over a wide range in some human
cells, suggesting that are much more toxic to some people
than to others. *2

Experts sponsored by the chemical and electrical power
industries acknowledge that. PCBs induce enzyme production, but
assert that this phenomenon merely demonstrates that the body is
dealing with intruding molecules in a natural and harmless way.
As General Electric puts it: ?Such effects are also produced by
many other substances, and are generally regarded as physiological
rather than pathological processes?. 3? .

I Pg.64
- 5 

1


 

1. Rickenbacher et a1., structurally! Specific Binding of
Halogenated Biphenyls to Thyroxine Transp'ort Protein, 29 Med
Chem 641 (1986) citing Yoshimura and Yoshihara, PCB Poisoning
anad Pollution, P. 57 (1976) - suggest that 3, 4, 
tetrach1orobiphenyl becomes significantLy more toxic inside the
body after the enzyme assisted substitution of an 0H (oxygen and
hydrogen) group for the hydrogen atom in the 5 position.
2. Calabrese, Methodological approaches to deriving environmental
and occupational healt standards, Wiley [(1977)
3. Ryan et a1., Separatio and characterization of highly
purified forms of liver micrbsomal cytochrome from .rats
treated with biphenyls, phenobarbital, and 2-
254 Biol Chem 1365 (1979); also: Parkinson
et a1., biphenyls as inducers of hepatic
microsomal enzymes: Structure-activity rules, 30 Chem Biol Interac
271 (1980).
4. Alvares et a1., biphenyls; A New Type of-
Inducer of Cytochrome p- -448 in the liver, 70 Proc Nat Acad Science
USA 1321; also: Bickers, Microscope Immersion Oils: Effects of
Skin Application on Cutaneous and Hepatic Drug-Metabolizing
Enzymes, 24 Biochem Pharmacol 779 (1975).
5. Goldstein et a1., -in a
Commercially Available 99% Pure Biphenyl Isomer
Identified as the Inducer of Hepatic Cytochrome P-448 and Aryl
Hydrocarbon Hydroxylase in theuRat, 6 Drug Metab Disp 258 (1978);
also: Nagayama et a1., Inducing Potency of Aryl Hydrocarbon
Hydroxylase Activity in Humani Cells and Mice by
Dibenzofuran Congeners, 59 Environ Health Persp 107
(1985)

6. Rosenblatt, A Possible Interaction of PCB and Halothane in
Man, 51 Anesthesiology 95 (1979).
7. Jaegar, Chemical Modification of Acute Hepatotoxicity of Vinyl
Chloride Monomer in Rats, 41 Toxicol 597 (1977); also: Murphy,
Potentiation of Fluroxene Toxicity with Biphenyls,

48 Toxicol Appl . Pharmacol 87 (1979)-

8. Shimada and Sato, Covalent Binding of 
Biphenyls to Rat Liver Microsomes, 55 Toxicol Appl Pharmacol 490.
9. Safe et a1., Relationships and

Mechanism of Action, 60 Environmnetal Health .Perspectives 47
(1985).

10. Roberts et- al., The Ah  Recptor and Dioxin Toxicity: From
Rodent to Human Tissues, 14 Chemosphere. 661 (1985);
11. Schecter it a1., Chlorinated Dioxin and Dibenzofuran Levels
in Human Adipose Tissues from Exposed and Control Populations In:
Rappe et a1., (eds), Chlorinated Dioxi-ns and Dibenzofdrans in
Perspective, page 51 (1986).
12. Nagayama et a1., Inducing Potency of Aryl Hydrocarbon
Hydroxylase Activity in Humanl Cells and Mice by
Dibenzofuran Congeners, 59 Environ Health Persp 107
(1985).

13. Brown et a1., Human Health Effects of Electrical-Grade.PCBs,
General Electric Company, Fairfield, Conn. (1981).

Pg.65

 earidi I>1.s5eeanssee

People who have suffered exposure to high levels of PCBs may .
be at increased risk of being harmed by other chemicals.I One
reason for this is that the victims of PCB exposure producie high
levels of enzymes which can rapidly change other chemicals into
potent toxins. Supporting this conclusion is the fact that PCBs
can drastically increase the teratogenicity of dioxin in rodents.?
There is also a study which shows that PCBs make grilled hamburger .
extract mutagenic to certain bacteria.2 A possible case of 
making a usually harmless anesthetic into a potent liveritoxin,
involving a woman who worked in a capacitor manufacturing plant,
has appeared in the medical literature.? The enzymes which PCBs
induce change some compound's to liver toxins,? some in_to
mutagens,5 some into embriotoxins,? and others into carcinogens.?
It has been shown that relatively non-toxic polybrominated
biphenyls greatly increased the toxicity of 1,2, 4,6,7?pentabromo-
naphthalene.?

A?nother proposed explanation of observed synergisms involves
the binding of PCBs to liver cell proteins which also binds toxins
such as dioxin. it is speculated that by tying up the receptor
protein binding sites, PCBs leave the other toxins free to do
harm.9 Another explanation involves impairment of the immune
system by 

A great deal of evidence that PCB exposure makes people more
vulnerable to the adverse effects of other chemicals comes from a
procedure called the "Ames Salmonella/microsome mutagenicty test,"
a procedure which relies on PCBs or other compounds too induce
enzymes.n In its simpler forms, the Ames test involves hdding
chemicals to bacterial cultures to determine whether the chemicals
are mutagenicu The Ames Salmonella/microsome mutagenicty' test
involves adding to the bacterial culture not only the chemical
being tested, but also an extract of this livers of rodents which
had been pre-exposed to PCBs or other enzyme inducing compounds.
In many cases, the compound being tested is mutagenic only in
combination with PCB induced enzymes.

Trichloroethylene, a once very popular degreasing solvent, may
be especially dangerous to persons who have been exposed to

Trichloroethylene was used in quantity at many capacitor
and transformer manufacturing facilities.

Pg.66

 

1

I
I


l. Birnbaum et al, Toxic Interaction of specific 
Biphenyls and 2, 3, 7, 8- -tetrach1orodibenzo?p?Dioxin: IncFeased
Incidence of Cleft Palate in Nice, 77 Toxicol Appl PhaFmacol
(1985); Also, Bandiera et al., Binding of Biphenyl
Classified as Either Pheno-barbitone, or
Mixed-type Inducers to Cyto?olic Ah Receptor, 39 Cheml Biol
Interact 259 (1932). 

 


2. Felton et a1, Mutagens in Cooked Foods -- Metabolism. and
Genetic Toxicity, 177 Adv Exp Med Biol 555 (1985)-

3. Rosenblatt, A Possible Interaction Of PCB and Halothane in
Man, 51 Anesthesiology 95 (1979).

4. Osimitz and Conolly, Mixed-functiOn Oxidase System Induction
and ?Propylene Hepatotoxicit y, 15 ?Toxicol Environ Health 39,
(1985), Rosenblatt, A Possible Interaction of PCB and Halothane in
Man, 51 Anesthesiology 95 (1979).

 

5. Welsh, Effects of Acute Chronic Biphenyl
Ingestion on Embryotoxicity Caused by Cyclophosphamide in Nice, 57
Arch Toxicol 184 (1985); Wild et al., Differential Mutagenic
Activity of IQ (2Amino- 3-methylimidazpld, 5-f11guinoline) in
Salmonella Typh-imurium Strains in Vitro and in Vivo, in
DrosoPhila and in Rice, 156 Mutat Res 93 (1985).

6. Greim et a1, 39 Falk 177, {1935); Talcott

et.a1., The Effect of Lead and Biphenyl Exposure
on Rat Natural Killer Cell Cytotoxicity, 7(2) Int 
Immunopharmacol 225 (1985).

7. Rosenblatt, A Possible Interaction 0f PCB and Halothane in
Man, 51 Anesthesiology 95 (1979).

8. McKinney et a1, Structure? ?Induction Versus Structure- -Toxicity
Relationships for Biphenyls and Related Aromatic
Hydrocarbons, 60 Environ Health [Perspect 57 (1985).

9. McKinney et al, Structure- -Lnduction Versus Structure-Toxi?city

Relationships for Biphenyls and Related Aromatic

Hydrocarbons, 68 Environ 57 (1985). -
I

10. Talcott et al., The Effect of Lead and 
Biphenyl Exposure on Rat natural Killer Cell Cytotoxicity, 7(2)
Int Immunopharmacol 225 (1985).

11. McCann et a1, Detection Of Carcinogens as Mutagens in the
Salmonelly/Nicrosome Test: Assay of 300 Chemicals, 72 Proc Natl
Acad Sci USA 5135 (1975).

12. Sato and Nakajima, Enhanced Metabolism of Volatile
Hydrocarbons in Rat Liver Following Food Deprivation, Restr-icted
Carbohydrate Intake, and Administration of Ethanol, Phenobarbital,
Biphenyl and 3- -Hethy1- cholanthrene: a Comparative
Study, 15 Xenobiotica 67 (1985).!

i Pg.87

2



?w-n



 




Ezeesseeairrc=?1

. 3

Enzyme determinations are usually performed on experimental
animals after they have been sacrificed. ?When the liver of the
experimental animal is homogenized and centrifuged (spun inga test.
tube), solid material goes to the bottom. The liquid onltop is
called :ytosol or cytosolic fluid; the particles on the theibottom
are called microsomes.?L 

Some of the enzymes whosl production is induced by PCBs are
found in the cytosol. These include the group of enzymesicalled
"cytochrome which are also involved in microsomal
processes. "Cyto-" tells where it is found, "-chrome" refers to
the fact that it is based on the iron containing pigment heme, and
"450" refers to a frequency of radiation which it readily absorbs.

Enzymes found in the sol ds at the bottom of the centrifuge
tube are. called 'microsomal? enzymes". Thus, references to
?hepatic microsomal enzymes" are not so much descriptions of the
enzymes themselves as they are descriptions of where the enzymes
were found in the animal (hepatic refers to the liver) andiin the
centrifuge tube. The micrbsomal portion is added to the cultures
in the Ames Salmonella/micrbsome mutagenicty test mentioned
earlier. 

- 

The degree to-which various dioxin-and PCDF congeners bind to
certain proteins found in the cytosolic fluid correlates with
their ability' to induce the actiVities of :various: drug
metabolizing enzymes; and it;.also correlates with ?their: acute
toxicity. Thus 2,3,7,84TCDD,jthe most toxic dioxin congener, is
the PCDD which binds most readily to the cytosolic protein, and is
also the most potent inducer of enzymes.

How and where enzyme induction takes place is unknown. Some
researchers believe that enzyme induction occurs after the toxin-
protein complex migrates toward the center of the cell into what
is called the cell "nucleus?. (This would have been before the
researcher remOVed, homogenized, and centrifuged the tissue or
organ, of course, and isn't easily verified in the lab.) Others
think it happens within minute budies inside the cell called
mitochondria.

The PCB congeners which bind to the cytosolic proteins are
extremely toxic. They are the congeners which most resemble-
in structure, ile., they have chlorine ?atoms on
either end and some ability to assume a planar configuration.

Little is known about'how the dioxins and the most toxic PCB
congeners cause sickness and death. It appears that the enzymes
which are induced are not the toxic agents because some potent
enzyme inducers are virtually non-toxic. Scientists continue to
investigate the_ puzzling link between toxicities_ of and
related Compounds and their abilities to stimulate the production
of certain enzymes in the hopeiof solving the mystery of how these
compounds cauSe.sickness and death in living organisms. 68

i 
1* 10 ..









 

 

1. The micrOSomes are primarily fragments of cell membranes and
'minute structures. called riboSOmes and mitochondria. Genetic
material is concentrated in ribosomes,.and it is ther'e that?
most protein take place. The mitochondria are
responsible for producing ene gy and are rich in fats, proteins,
and enzymes. I

Safe, Biphenyls and Polybrominated Biphenyls:
Biochemistry, Toxicology, and Mechanism of Action, 13(4) CRC Crit
Rev Toxicol 319 (1985).

'HcKinney et a1., structure - Induction Versus Structure Toxicity

Relationships for Biphenyls and Related Aromatic
Hydrocarbons, 60 Environ Health Perspect 57 (1985).1
Neil, Mechanisms of the Biological Effects of PCBs,
D1benzo-?p-dioxins and 
Dibenzofurans in Experimental fnimals, 60 Environ Health Perspect
41 (1985)

1

Safe .et a1., S-tructure-Functifon Relationships and Mechanism of
Action, 60 Environ Health Perspect 47 (1985). 

 

Pg. 69
i

I



EDC3I3 rdeLizailocaiLilizeess
Metabolism is the sum of all the chemical processes inside the?

body which release energy from ingested substances; mainly, food.
These reactions are the basis of life. Some of these reactions-

involve the addition 0f atoms to organic (carbon 

containing) compounds in order to produce energy. This is similar
to the way oxygen adds to burning substances to produce energy,
only the reactions in the body?are controlled by enzymes.

In a broader sense, "metabolism" can include all chemical
reactions inside the body, including removing or rearranging atoms-
in a molecule. As was mentioned earlier, whenever a molecule is
transformed into another molehule inside the body, the original

molecule is called a "substrate" and the new molecule is called a
"metabolite".

PCB congeners with hydrogen atoms in adjacent positions tend
to be most readily metabolizedL 8 hours after injection of highly
toxic 3, 3'4, 4'?tetrachlorobipheny1 into rats, 90% of the compound
had been transformed into two metabolites. One of these
metabolites was found to very active in suppressing levels of
Vitamin A and thyroxin, a hormone produced by the thyroid gland.?

Sulfur containing PCB metabolites accumulate in the lungs,
and may be responsible for the respiratory distress and reduced
vital capacity associated. with exposure to PCBs. other PCB
metabolites, called arene oxides, are of interest because some
arene oxides are proven carcinogens.

PCB metabolites are primarily of interest to research

scientists. Levels of these compounds are not commonly measured
in exposure victims.

1. Brouver and Berg, Binding of a Metabolite of 
tetrachlorobiphenyl to Reduces Serum vitamin A
Transport by Inhibiting the .Formation of the Protein Complex

Carrying Both Retinol and Thyroxin, 85 Toxicol Appl Pharm 301
(1986).

 

 .
.1

3'

lig?rqi

in?rm?m} -

13-1Chlorinated Dioxins and Dibenzofurans in Perspective, Christ'offer Rappe, Gangadhar

INTRODUCTION .

Choudhary, Lawrence H. Keith, Lewis Pub. (30., Inc., 1986.



 

dibenzo-p-dioxins and furans are
well known environmental contaminants. A number of laboratories have 
many of the PCDD and PCDF congeners'for analytical reference material. Some
of these congeners are also available commercially. A review of the environmental
chemistry literature, as well as publicationsl of commercial firms, showed that another
class of potentially toxic chlorinated aromatic compounds is not available: the
biphenylenes The are closely related -TCBP isomer has been studied by Poland et al. and found
to haire about the same degree of toxicityl as 2, 3, 7, 8-TCDD. Rappe et al. reported
on two accidental PCB fires in Sweden. In the fire where oil-filled capacitors burned,
were the main products formed. In another capacitor fire
(possible electrical malfunction), were the main products. The only PCBP
isomer available as a reference for this study was the 2, 3, 6, 7- -.TCBP Williams
et al. described results from four PCB fires in which the were present, at
concentrations 10 times higher than the In fact, these researchers found
that were the main chlorinated species present, excluding the P035. Smith
et al. also reported finding a large number of in soot produced during: an
electrical accident that involved the pyrolysis of PCBs in a state office building
in Binghamton, New York, in 1982. Since analytical standards for the chlorinated
biphenylene congeners are not available, we have prepared them by either photolysis
of octachlorobiphenylene (OCBP) or chlorination of biphenylene. (pp. 501-502)



 

Pg. 71

 ?Zack, Judith A. and David- C. Musch; "Mortality of PQB Workers at the Monsanto Plant
in Sauget?, Illinois"; December 14, 1979;-p. and Table [Private study of Monsanto Company, not published.]

 

saturates-states:

 

An historical prospective mortality study was conducted on. workers exposed
to biphenyls at the Monsa?nto Company plant in. Sauget, Illinois.
Eighty-nine workers exposed to PCBs for a inimum of six months during the period
1945 to 1965 were followed for their mortality experience. Observed deaths were
not statistically different from expected de for. any of the cancer sites examined.
No deaths were observed from cancer of the liver or pancreas or from malignant
melanoma. No excess was seen in deaths from liver cancer. A statistically significant
excess of circulatory disease, exclusive of larteriosclerot-?ic heart disease, was seen
in white males. 

i
if


i

Pg. 72 

 

Table 4

Observed and ERpected Deaths, All Males

 

 

 

 

IOCOD. NO. 
jEighth Rev.) Cause of Death Observed Expected ?55
All causes of death 30 22.88 131
140-209 A11 malignant neoplasms 8 4.46 179
140-149 Buccal cavity and pharynx 0 0.16 -
150-159 Digestive organs and peritoneum 1 1.33 75
- All other digestive organs 1 1.23 81
160-163 Respiratory system 4 1.53 261
162.163 Lung 4 1.44 278
- All other respiratory organs 0 0.09 -
185-189 Genitourinary organs wLm__m_ 1 
Lympatic and hematopoietic tissue 1 0.40 250
-- Other sites 1 0.53 189
390-458 Diseases of the circulatory system 16 11.17 143
410-413 Arteriosclerotic heart disease 7 7.19 97
- All other diseases of the circulatory system 9 3.98 226*
460-519 .Diseases of the respiratory system 1 1.27 79
520-577 Diseases of the digestive syStem 2 167
- All other diseases 2 2.40 83
800-998 External causes of death 1 2.38 42

 

Number of persons observed 2 89
(.05

 

82; ?3d

bz'?d



HISTORY OF OR 

(Preliminary Information)

NAME:

 

STREET
ADDRESS:

 

CITY:

 

STATE: . . ZIP:

 

TELEPHONE: 

 

 

DATE OF BIRTH:

 

SSN:

 

 

YEARS OF EXPOSURE TO P683: to

PLACE OF EXPOSURE TO PCBS:

 

 

The or conditions included in this checklist, except
where indicated otherwise, were used in a 1977 PCB occupational
exposure study ore-pared by NIOSH, 11.3. Deot. of Health and Human
Services. n?

 PAGE 90.1: no

,7

Chronic




ma.mm

EALTH
Heart
Elevated
blood

Sudden,

YMPTOM OR
CONDITION
Coughing
Wheezing
unexplained

tightness
Stroke?
attack?

pressuref
Sudden,,
unexplained
shortness
of breath
shortneSs

of breaththe chest 


OR
3--

 

CONDITION

Before
to PCBs

Exposure

 

IF YOU DID EXPERIENCE THE
OR CONDITION,
IT FIRST -
During


 

Exposure
to?PCBs

After

Exposure
to PCBS

WHEN DID




 

 



IS THIS A
CURRENT
YMPTOW OR
ONDITION



I


--

septa-TREATMENT BY
.DOCTOR FOR
OR
CONDITION

 

.-
.



.
at I. o. no




.. 

I




PRESCRIPTION
OR OVER-THE-

MEDICATION


OR CONDITION


4 PAGE 3 -

9L'3d

to light?

 



Eyes are
sensitive

 

I. I. ..



2
8

irritation?

Nose

eyes


Irritated
or burning

 

 

Headache

 

1

Light-

heaqedness
Dizziness?

 

 

 

 

VOmiting

Chronic



reathing
roblemsf

Yes 2

CONDITION

Exposure 
to'PCBs

Exposure
to'PCBs to?PCBs

Exposure

No

No

CONDITION 




EALTH
YMPTOM CONDITION,
IT FIRST 
Before 

IF YOU DID EXPERIENCE THE

During

After

WHEN DID




IS THIS A
URRENT
YMPTOM OR

CONDITION

0
I



I

.

TREATMENT BY
DOCTOR FOR
OR
CONDITION

PRESCRIPTION
0R OVER-THE-
COUNTER
MEDICATION
FOR 
OR CONDITION

a. no I. O. IIJO O.



I


CONDITIONS Checklist

?5 

- 'S'x morons/coqu-mu? "chem?mtIPISONI C. . 
MmeaRuu? 
P0CMW0.MROT. . 
TOTI. . . 
ATPDSTEITRPD. 3. . . . 
.
LCSCroc93CEnua._ .
PMR. rxo. . .
W00. uE . .
.CCrm?. mmpIMI. BatNHSOC0N. eif.Y .o .o t. ab 
0_ev1t.1 e. da. da. rn rm 
.MI_ri h?l t_9ee 9e9_gowfm ete .
HOT.att9.a i.nth nti_n 601.1nma.
TTI. ihi_u t_i?r 1at_1dd t_bee9_
LPD_ssgn_sre.tmer tms.1e_t _ucrn.
mmunmmutummwugPAGE 4 -

- PAGE 5 -

2. .mm



Swelling of
fingersf



were swollen 

 


2
8
I
3

thOugh
feet

Feeling as

 

 

 

Discharge

i



nflammation 

 

 



,were swollen 

eyelids

FEeling as
though

irritable

 



eeling

reguently
tense and




CONDITION to PCBs

Exposure

Exposure
_to PCBs



CONDITION


0R

During
Exposure 
to PCBs

After

No

2 Yes

No

OR CONDITION

EALTH

Before




OR 
CONDITION

OCTOR FOR
OR
CONDITION

TREATMENT BY 


MEDICATION
FOR 

VER

OR CONDITION.
IT FIRST 

IF YOU DID EXPERIENCE THE

WHEN DID 2 CURRENT

IS THIS A

COUNTER

PRESCRIPTION
OR OVER-THE-

- '2

Checklist~

-

I 
a 
.4 

PAGE

I. 00 it cone. 
ll

mm

5:95

0





sex




6









arkening
in

Decreased?
interest

L?3d

EALTH

nusual

33 of
sensitivity
to the

smell of

.YMPTOM OR
CONDITION
ingernails
ardening of 
oenailsf
oenails
eformedf
Bloody or
red urine
nse of

Increased
chemicalsf

 

$EVER

OR

 

CONDITION

nun-nu nauoccoo' u?

 

 

Before

 

Exposure
to PCBs

OR CONDITION,
IT FIRST 

IF YOU DID EXPERIENCE THE
During
to PCBs

Exposure
2

 

 

After
to PCBs

Exposure

WHEN DID

3
3
3




IS THIS A
CURRENT

Yes 

YMPTOM OR 
ONDITION

DOCTOR



I. I. II

I

OR
CONDITION

TREATMENT PRESCRIPTION 
OR OVER-THE-
COUNTER
MEDICATION
FOR 
OR CONDITION

No



 

I


.



3
3

 

1.

'?sfi?wbus

'7



U.
f.

44





CONDITIONS th?exriar

- PAGE 7 -

3
2
3



9

dark patches
of skin

Skin

om.mm

EALTH
Swelling in
_jointsi


chest?

Unusual
Redness of
skin on

perform



Inability to 

.YMPTOM OR
CONDITION
sexually?
WEak muscles 3
Jaundicef

Arthritis or

 

discoloration?

 

OR

HAD


NEVER

 






2
I

CONDITION 

 

 

Before
to?PCBs

Exposure


 

3
2

OR CONDITION,
IT FIRST 

IF YOU DID EXPERIENCE THE
During
Exposure
to?PCBs

I. I. I. I.

WHEN DID
After
Exposure
to PCBs

 

 

.
.. 


9
I



I


IS THIS A
CURRENT
OR 
CONDITION

2 
3 

 

No
2

REATMENT BY
OCTOR FOR
OR
CONDITION

0R CO

FOR 


.000

a











?l .


OVER-THE-
COUNTER

RESCRIPTION

MEDICATION



NO

 

sxu?rous/counrwxous checklist
JDITION

 

 

- PAGE 8 -

Hm.um 

 





eal well

ores that
0 not

Shooting
ins in
knees?

 

 



 





o. I. I.

 

loss or
diminished
sense of
touch


Unexplained

2
2
3
8
8



tingling

Unexplained
hands

CONDITION 

Exposure




EALTH
YMPTOM OR
CONDITION

3 0R

HAD


Befdre
to PCBs

CONDITION,
IT FIRST 

IF YOU DID EXPERIENCE THE
During
Exposure 
to PCBs

After
Exposure
to?PCBs

WHEN DID

I

IS THIS A

CURRENT

DOCTOR FOR
OR

- CONDITION
Yes

No

0R 
COUNTER
MEDICATION

Yes


No

OR CONDITION

TREATMENT BY PRESCRIPTION
FOR 

 

 

NS CHEEKIIE



CONDITIO

- PAGE 9 -

3


i

sweatingf

kin

um.mm

rritatiOnf

HEALTH

 

OR
CONDITION

pimples
dermatitis

."Unexplained
itching
Frequent
abdominal
Profuse

Skin rash or 
Unexplained

 

Unexplained
weight loss

 

HN
V.
a

weight gain? 

0R

EVER


 

CONDITION

2
3

 

Before
Exposure
to PCBs

YOU DID EXPERIENCE THE
OR CONDITION,
IT FIRST 

During

to PCBs

Exposure

WHEN DID
After
Exposure
to'PCBs

 



Yes


IS THIS A

- CURRENT
OR 
CONDITION

2 


OCTOR FOR
OR
CONDITION

REATMENT BY

 

NO



.8
.S



0.

COUNTER

OR OVER-THE- 
MEDICATION




- PRESCRIPTION
FOR 
OR CONDITION

 

 

L~Checklist

- PAGE 10 -

Back pain?




sa?d

EALTH
Personality
change?
Memory
loss?

.?Frequen

colds?
Sudden,
onset of
Non-cancerous:
tumors?

weakehing
of grip?

I.


CONDITION

YMPTOM OR
Nervousness? 
allergiesHAD


NEVER
CONDITION

 

 

Before

 

Exposure
to'PCBs

 

 

IF YOU DID EXPERIENCE
OR CONDITION,
IT FIRST 

 

Durinq
Exposure
to P088

2
2

THE
After
Exposure
to PCBs


WHEN DID

I
2

 

IS THIS A
CURRENT
OR
CONDITION

TREATMENT BY

DOCTOR FOR

OR

CONDITION


 

PRESCRIPTION 
on OVER-THE-
COUNTER

 

 

MEDICATION

FUR 

OR CONDITION
N0-Mll

I rug--



- PAGE 11 -

PB

amagef






0


age?

older than

?a.ma

irth
Peeling of
skin on
.feetf


Immune

EALTH

YMPTOM OR
CONDITION

efects in
children?



ystem

hair?

Unusual
Difficulty
sleeping?
Feeling

 

nusual loss 


CONDITION ,to PCBs

Exposure

 

Before?

I. D. I. 

OR CONDITION,
IT FIRST 

IF YOU DID EXPERIENCE THE
During

 

Exposure
to PCBs


2
2
I
2
3

After
Exposure
to PCBs

WHEN DID

Yes 3 No

3
2
2

IS THIS A
CURRENT

 

OR
CONDITION

1


 

Yes



.BATMENT BY
DOCTOR FOR
OR
CONDITION

3

No


3 Yes

OR CONDITION
2
8

PRESCRIPTION

OR OVER-THE-

COUNTER

MEDICATION

FOR 


No

 

 

 

i
-mJ

- 



checklist

. ?I-nmeygr- 
.. 



- PAGE 12 -

I
HIMOQ



1.

Shoes

98?3d

hemical

mell

rom work?
2 

HEALTH


OR

CONDITION
ollapsed
eteriorated
chemicals 
at work?
Health
problems
with no
medical
explanation? 

2 
2 0R


El:
3'


NEVER

 

3 CONDITION



 

 

 

Before

xposure
3
2


to PCBs 1:

IF YOU DID EXPERIENCE THE
OR CONDITION,
IT FIRST 

During

PCBS

xposure

After
Exposure
to?PCBs

WHEN DID

I




 

 

2 Yes

5 THIS A
URRENT
YMPTOM OR 
ONOITION

TREATMENT BY
DOCTOR FOR
OR
CONDITION

COMIC-0.. 

This symbol indicates a or condition which did not appear in the 1977 NIOSH study.

PRESCRIPTION 8
0R OVER-THE-
COUNTER

MEDICATION
FOR 

CONDITION

 


.
2