12. Toxicology and Health Impact of PCBs

by Dr. Gnther Neumeier

1. Introduction

Polychlorinated biphenyls (PCBs) are chlorinated aromatic hydrocarbons. They are manufactured by progressive chlorination of biphenyl in the presence of a suitable catalyst. Depending on the reaction conditions the chlorination can lead to the replacement of 1 -10 hydrogen atoms by chlorine.

The general formula can be given as:

C12 H10-n Cln ( with n = the number of chlorine atoms)

With respect to the different number of chlorine atoms and the different positions they can have in the molecule, theoretically 209 compounds (isomers and congeners) are possible. About 130 of these are likely to occur in commercial products or mixtures. The toxic effects and the environmental behaviour of these mixtures are highly dependant both on the degree of chlorination and the position of the chlorine atoms of the biphenyl. The so called "coplanar PCBs", these are the non-ortho -,the mono-ortho-and the di-ortho chlorinated derivates of PCB, resemble more or less the qualitative toxicological properties of the 2,3,7,8 substituted Chlorodibenzodioxines ( Parkinson and Safe, 1987). As all technical mixtures of PCBs undergo a change in their composition when released into the environment and research with real environmentally relevant mixtures are scarce, most of the toxicological research has been performed with relevant technical mixtures of PCBs, as for instance Aroclor 1254. The following gives an overview of the toxic effects in animals and the health impact of PCB-mixtures.

Acute Toxicity

Animals:

The acute toxicity is low

-depends on the degree of chlorination of the technical.mixture and the species tested.

LD50(oral) for rodents :1-11g/kg bw

LD50 (dermal) for rabbits : 1-3g/kg bw

However:

Dioxin - like congeners as 3,3’,4,4’ Tetrachlorobiphenyl elicit a much higher toxicity

-e.g.LD50(oral) for guinea pigs :<1 mg/kg bw

 

Subchronic/Chronic Toxicity

Animals(1):

Repeated doses of PCB applied to experimental animals up to 90 days (subchronic) or up to 2years/livetime demonstrate the full toxicological fate of this group of substances:

-there is a latent period until the onset of signs of toxicity (1week-1month)

-females are often more susceptible than male

-young animals show a higher susceptibility than adult ones

-there are marked differences in the sensitivity of various species (monkey/mink> rat/mouse > hamster) and strains (C57BL mice >DBA mice) of animals.

 

Subchronic/Chronic Toxicity

Animals(2):

Although the differences mentioned before, there are common responses to PCB intoxication:

-wasting syndrome

-skin disorders

-hyperplasia of epithelial cells of the bile duct, gall bladder and urinary tract

-lymphoid involution: thymic and splenic atrophy

-immunotoxicity

-liver damage

-porphyria

-endocrine and reproductive dysfunction

-teratogenic effects: kidney, cleft palate

-carcinogenic effects: e.g. hepatocarcinoma in rats and mice

Subchronic/Chronic Toxicity

Animals(3):

From numerous experiments on various species investigating different technical mixtures and toxicological endpoints, the following LOAEL’s / NOAEL’s (mg/kg bw/day) can be derived (according to ATSDR 1996):

 

Mouse

Rat

Mink

Monkey

LOAEL

serious

50 - 13

72.4(leth) -1.25(ca)

2.8(leth) -0.2(leth)

4(leth) -

0.1(inf,leth)

LOAEL

less ser.

12.5 - 5

32.8(bw) -

0.09(T3/T4)

n.a.

0.03(inf,bw)0.005(IGM)

NOAEL

1.25 - 0.5

5 - 0.05

0.9 - 0.1

0.08-0.007

 

 

Other Toxicological Endpoints

Animals(4):

Mutagenicity:

In vitro:

PCB mixtures did not cause mutation or chromosomal damage in a variety of test systems although adducts with DNA,RNA and proteins could be detected (prior metabolisation is necessary)

In vivo:

Besides some inconclusive results, PCB’s showed no mutagenic activity in the tested animals.

 

Other Toxicological Endpoints

Animals(5):

Carcinogenicity:

According to the evaluation of IARC (1987) of PCB-mixtures there is sufficient evidence for carcinogenicity to animals.

The PCB’s caused benign and malignant liver neoplasms in mice and rats after oral administration.

Recent studies (Silkworth et al. 1997) confirmed IARC’s evaluation and showed that

-the potency of Aroclors is 1254 >1260 = 1242 >1016

-female rats are more susceptible and liver carcinogenesis is TEQ dependent

-male liver tumors are not TEQ related (2 different mechanisms ?).

Summary of Symptoms of PCB Intoxication

Although there are marked species,age and sex differences, the toxic responses to PCBs resemble some general effects:

  1. Wasting Syndrome: progressive weight loss, not related to food consumption;

2. Skin Disorders: chloracne, edema, hyperkeratosis, alopecia, hypertrophy of the Meibomian glands;

3. Hyperplasia of epithelial cells: extrahepatic bile duct, gall bladder, urinary tract;

4. Lymphoid involution: thymic and splenic atrophy (immunosuppression, bone marrow and haematologic dyscrasias);

5. Liver damage: hepatomegaly, necrosis, hemorrhage and intrahepatic bile duct hyperplasia;

6. Porphyria: disordered porphyrin metabolism

7. Endocrine and reproductive effects: altered plasma levels of styroid and thyroid hormones with (a) menstrual irregularities, reduced conception rate, early abortion, excessive menstrual and postconceptional haemorrhage and anovolution in females, and (b) testicular atrophy and decreased spermatogenesis in males;

8. Teratogenesis: cleft palate and kidney malformations

9. Carcinogenesis: hepatocarcinoma

The underlined effects / toxicological endpoints are also seen in humans.

Acute Toxicity

Humans:

-acute oral and dermal toxicity is low (as in animals),

-vapour concentrations at the workplace (1mg/m or less) do not cause immediate toxic effects,

- no lethal doses for any route of exposure can be given,

- first symptoms within a few hours after high exposure are

skin rash, burning sensations, itching and irritation of the eye.

However:

Even single dosages can cause subacute, subchronic and chronic effects (similar to smaller repeated doses) as there are:

chloracne, hepatitis, facial oedema, numbness, weakness of extremeties, pigmentation of fingers and nails.

Subchronic/Chronic Toxicity

Humans(1):

Main information:

-accidental exposure at the workplace

-occupational exposure

-accidental poisoning of consumers with contaminated rice oil (Yusho/Japan 1968;Yu-Cheng/Taiwan,1978/1979)

General remark:

Assessment of human health effects is difficult because of the coexposure to other substances (e.g.PCDF’s), the frequently unknown composition of the PCB-mixture and the real amount of exposure to PCBs. Although effects seen in humans are generally more meaningful for the risk assessment - in the case of PCB one should be very careful in using human data.

 

 

Subchronic/Chronic Toxicity

Humans(2):

Occupational Studies:

-major route of exposure : inhalation (up to 16 mg/m)

- dermal exposure is also likely (up to 28mg/m measured)

-most studies investigate male workers from electrical industries.

Effects:

-skin lesions, chloracne,

-estimated threshold conc. chloracne :0.2mg/m (Safe,1987)

-respiratory effects: irritation of upper resp.tr., chest-tightness

-GI-tract: loss of appetite,epigastric pain

-hepatic effects:serum levels of liver -related enzymes

-endocrine effects: thyroxine (T4) (max 0.012mg/m /4y)

Subchronic/Chronic Toxicity

Humans(3):

Occupational Studies:

-Neurological effects: headache,dizziness,depression etc.

-Developm. effects: birth weight of infants ,shorter gestation

-Genotoxic effect: no clear results but some indications (chromosomal aberrations in lymphocytes,SCE )

-Carcinogenicity:

At least 5 mortality studies for occupationally exposed workers have been recently reviewed (ATSDR 1996). They are classified as ‘inconclusive’- although some evidence for a carcinogenic activity, especially to hepatobiliary cancer has been seen - because of the inherent limitations of the studies.

The IARC classification is: Limited evidence for carcinogenicity to humans.

Subchronic/Chronic Toxicity

Humans(4):

Yusho and Yu-Cheng = Rice Oil Diseases

Yusho, Western Japan (1968):

Mass poisoning by ingestion of rice oil contaminated with

PCB,PCQ,PCDF and traces of PCDD

1862 persons affected, 149 deaths until 1990.

Yu-Cheng, Taiwan (1978/1979):

Mass poisoning by ingestion of rice oil contaminated by heat degraded PCB.

2061 persons affected, deaths: ?

Exposure in Yusho (about 1g PCDF,150/150g PCB/PCQ /kg bw/d) and Yu-Cheng was similar.

Subchronic/Chronic Toxicity

Humans(5):

Yusho/Yu-Cheng:Effects and Symptoms

-latency period: 20 - 190 d, mean: 70d

‘Early’effects:

Hypersecretion Meibomian glands, pigmentation of nails mucous membranes,hyperceratosis,pigmentation, chloracne.

Effects on newborns:

-stillbirth ,birth weight ,skin pigmentation,gingival hyperplasia,oedemas,dentition at birth,abn.calcific. of skull =

Fetal PCB Syndrome (FPS).

‘Late effects’:

-Mortality (circulatory system,resp.system,digestive system)

-Liver cancer (Yusho: men 6-fold, women 3-fold)

 

Comment on Human Effects

Most of the information on the effects of PCB-mixtures is -from commercial mixtures not from mixtures typical for the environmental media, the different foodchains or food,

-coexposure to other harmful substances is scarcely controlled

-some mixtures have been definitely contaminated with more toxic substances (e.g.Yusho,PCDF’s),

-dose-response relationships are rare (doses are mainly calculated and not measured),

therefore these informations have restricted value for quantitative risk assessment.

However:

The qualitative information on effects gives a lot of information which experimental animals should be used for the risk assessment.

Rationale for the selection of Rhesus Monkeys as appropriate species for Risk Assessment

As long as PCBs are not clearly classified as carcinogens, noncarcinogenic endpoints should be used for Risk Assessment. The toxicological profile in experimental animals and humans

should be similar. Livetime or generation tests are to be preferred. The exposure pathway must be the same and relevant. The applied substance and dose has to be relevant for human exposure.

As most of the requirements listed above are in line with the experiments performed with monkeys and because of the similarity of general effects seen in humans, together with the phylogenetic relatedness of monkeys to humans, the experimental results obtained with rhesus monkeys are especially meaningful for health evaluations.

Health Risk Assessment

(Germany)

In Germany there have been two assessments

Lorenz / Neumeier (1983) :

Basis: Reproductive effects in monkeys (oral application of Aroclor 1248, Allen et al.1979)

NOEL: 16 g/kg bw, SF: 20

ADD (acceptable daily dose): 1 g/kg bw

Deutsche Forschungsgemeinschaft (DFG,1988)

Basis: Carcinogenic effects in rats (feeding study with Aroclor1260, see DFG 1988)

LOAEL: 5 mg /kg bw, SF: 5000

ADD: 1 g/ kg bw

The above assessment has also been taken into account.

The above mentioned Acceptable Daily Dose ( ADD ) of 1g PCBs/ kg bw is still valid for Germany.The actual exposure of adults in Germany has been recently estimated as to be between 0.1 and 0.05 g/kg bw /d. So, a reasonable margin of safety - at least for adults - seems to exist.

More recent research focussed on pre-, peri- and postnatally low level exposed children.

Some of these studies and their findings are shown below:

Effects of Low-Level PCB Exposure

(Recent Studies / Humans) (1)

1)Reproductive Effects:

a) Lower birth weight: Industr. region; Serpukhof; Russia (B.A.Revich,1997)

Rotterdam; Background level of PCBs/Dioxins; (S. Patandin,1997)

Fishconsumers;BalticSea;Sweden(L.Rylander,1996; L.Hagmar,1997)

Fish consumers; Lake Michigan; (Fein,1984; Jacobson,1990)

b) Spontaneous abortions:Industr. region; Serpukhof; Russia

(B.A.Revich,1997)

c)Congen. malformations: dto

d)Miscarriage: dto

 

Effects of Low-Level PCB Exposure

(Recent Studies / Humans)

(2)

2)Developmental neurotoxicity:

a)Cognitive development: Rotterdam; Background level of

PCBs/Dioxins; (S. Patandin,1997)

Fish consumers;Lake Michigan;

(Jacobson,1996)

b)Behavioral dysfunction: North Carolina;Background level;

(Rogan,1991)

Effects of Low-Level PCB Exposure

(Recent Studies / Humans)

(3)

3)Immunological effects:

a) Enhanced infectionrate See e.g. Tryphonas,1995

b)Reduced NK-cell activity

c)Altered plasma Immunglobulins

Effects of Low-Level PCB Exposure

(Recent Studies / Humans)

(4)

4) Hormonal Effects:

a) Thyroid hormone Review’s see:

S.P. Porterfield (1998)

E.S. Sher et al. (1998)

Conclusion:

As just indicated, it is still believed that the present ADD in Germany for PCBs of 1g/ kg bw is a save level, at least for adults. However, the recent studies of children-low level exposed pre-,peri- and postnatally-have to be carefully evaluated, together with studies to be finished in the near future, and checked whether the present ADD is also protective for unborn and newborn babies.

 

References:

ATSDR (1996) Draft Toxicological Profile for Polychlorinated Biphenyls (update), Atlanta, Georgia, Agency for Toxic Substances and Disease Registry.

DFG (!988) Polychlorinated Biphenyls. German Research Society: Communication XIII of the Government Committee on the Testing of Residues in Foods, Weinheim, Verlag Chemie (in German)

Fein, G.G. et al.(1984) Prenatal exposure to polychlorinated biphenyls: effects on birth size and gestational age. J. Pediatr.,Vol. 105, p 315-320.

Hagmar, L. et al. (1997) The concentration of 2,2’,4,4’,5,5’-hexachlorobiphenyl (CB - 153) in plasma in Swedish female fish consumers as a biomarker for risk of low birthweight. Organohalogen Compounds, Vol. 34, p 470.

IARC. (1987) Overall evaluation of carcinogenicity: An updating of IARC monographs Volumes 1 to 42, Lyon, International Agency for Research on Cancer, (IARC Monographs on the Evaluation of the Carcinogenic Risks of Chemicals to Humans, Supplement 7).

Jacobson, J.L. et al. (1990) Effects of exposure to PCBs and related compounds on growth and activity in children. Neurotoxicol. Teratol., Vol 12, 319-326.

Jacobson, J.L. and Jacobson, S.W. (1996) Intelectual impairment in children exposed to PCBs in utero. New Engl. J. of Medicine, Vlo 335, p 783-789.

LORENZ, H. and NEUMEIER, G. (1983) Polychlorinated biphenyls (PCBs). A joint report of the Federal Health Office and the Federal Environmental Agency. Munich, MMV Medizin Press (BGA Publication No. 4/83) (in German).

Patandin, S. et al. (1997) Birth weight and growth in Dutch newborns exposed to background levels of PCBs and Dioxins. Organohalogen Compounds, Vol. 34, p 447.

Patandin, S. et al. (1997) Pre- and postnatal exposure to PCBs and Dioxins and cognitive development of Dutch children at 3 years of age. Organohalogen Compounds, Vol. 34, p 451-454.

Parkinson,A and Safe,S (1987) Mammalian Biologic and Toxic Effects of PCBs in:Environ.Toxin Series. Vol 1, p.49 - 75, Springer-Verlag Berlin Heidelberg 1987.

Porterfield, S.P. and Hendry, L.B. (1998) Impact of PCBs on thyroid hormone directed brain development. Toxicol. Industr. Health, Vol 14, p 103-120.

Revich, B.A. et al.(1997) Polychlorinated Biphenyls (PCB) in the Ambient Environment and Reproductive Disorders in the Town of Serpukhov (Russia).Organohalogen Compounds, Vol. 34, p 429.

Rylander, L. et al. (1996) Consumption of fish from the Baltic Sea contaminated with persistent organochlorine compounds and low birthweight. Organohalogen Compounds, Vol. 30, p 218.

Safe,S (1987) PCBs and Human Health in:Environ. Toxin Series Vol 1, p 132 - 145, Springer-Verlag Berlin Heidelberg 1987.

Sher, E.S. et al. (1998) The effects of thyroid hormone level and action in developing brain: Are these targets for the actions of PCBs and Dioxins? Toxicol. Industr. Health, Vol 14, p 121-158.

Tryphonas, H. (1995) Immunotoxicity of PCBs (Aroclors) in relation to Great Lakes. Env.Health Persp,. Vol 103, Suppl. 9, p 35-46.