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The Monkey Studies - Reproductive Effects

The 9 studies below show serious PCB effects on reproduction; however, none of these studies examined PCB effects on male monkeys’ reproductive ability. In addition, none of the studies followed the offspring of PCB exposed mothers to determine whether the offspring had reproductive changes. Most studies used only PCB commercial mixes (Aroclor 1254 or 1248), not the more toxic PCBs accumulated up the food chain. This is not a complete list of all such research, only a sample. For additional study results, visit the TOXNET databases. (See also the Monkey Infant Studies)

Summary of PCB effects on monkeys

increased stillborns, fetal death, spontaneous abortions (miscarriages), or resorptions of the fetus (6 studies)
infertility or reduced conception (5 studies)
prolonged menstrual and estrous cycles, or absent cycles (4 studies)
reduced progesterone and estrogen hormones, and elevated follicle stimulating hormone (3 studies)
lack of ovulation or double ovulation --- PCBs interact with ovarian steroidogenesis (3 studies)
dose-dependent effect of PCBs on reproductive parameters (2 studies)
high infant mortality
low birth weight offspring
serum triglyceride, cholesterol and total lipids decreased
reproductive effects are seen in monkeys at PCB levels of 0.12 mg/kg/day.

The Monkey Studies

Study #1

estrogen values below normal
elevated follicle stimulating hormone
lack of ovulation or double ovulation --- PCBs interact with ovarian steroidogenesis

The effects of hexachlorobenzene (HCB) and polychlorinated biphenyls (PCBs) on sexual hormones were studied in rhesus-monkeys. Sixteen mature female monkeys were divided into treatment groups: four for HCB, four for PCB, four for vehicle controls, and four untreated. HCB and PCB were administered by gastric intubation in 1 percent methyl-cellulose suspension in water at a dose of 4 milligrams per kilogram (mg/kg) per day. Serum luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone, and estrogen concentrations were monitored throughout a monthly cycle. The effects of HCB and PCB on ovarian steroidogenesis were also examined in female rats. Following pretreatment with pregnant mare serum and human chorionic gonadotropin, rats were given 20mg/kg HCB by subcutaneous injection. Two days later, rats were sacrificed and ovaries were incubated with LH. Progesterone production was measured. In monkeys treated with PCB and HCB, LH values remained normal. Some of the treated monkeys showed elevated FSH production in the latter phase of the cycle. No progesterone rise was seen in some treated animals indicating an absence of corpus luteum. Most PCB treated monkeys showed estrogen values below normal. Two of the PCB treated monkeys did not ovulate, and one had a double ovulation. One HCB treated monkey did not ovulate. Both HCB and PCB treated rats had increased progesterone production after stimulation with LH. The authors conclude that treatment with HCB and PCB lowers estrogen production in monkeys and interacts with ovarian steroidogenesis in rats. Accelerated liver metabolism may cause estrogen reduction. (Muller et al, 1978)

Study #2

duration of menstruation increased, or absent
decreased conception
increased abortions (miscarriages) and resorptions of the fetus
increased stillborns
serum triglyceride, cholesterol and total lipids decreased
changes were dose-dependent
study used PCB commercial mixture Aroclor 1248

The effects of low concentrations of polychlorinated biphenyls (PCB) on reproduction were studied in monkeys. Menstrual cycles, sperm counts, and morphological spermatozoa features of adult Rhesus-monkeys were evaluated for 6 months. Monkeys received 2.5 or 5.0 parts per million (ppm) Aroclor-1248 (12672296) in the diet. After 7 months, females were mated with control males and males were mated with control females during a 5 day period. Animals were observed daily and were weighed monthly. Serum chemistry was determined monthly. At intervals, an inguinal subcutaneous fat biopsy was taken from selected animals and evaluated for PCB. Experimental groups lost an average of 15.1 percent of their initial weight in 6 months with constant diet intake. Animals ingested about 90 and 180 milligrams (mg) PCB on the 2.5 and 5.0ppm diets, respectively. Within 2 months of the experiment, animals began showing typical signs of PCB intoxication. Serum triglyceride, cholesterol, and total lipids decreased progressively. The total lipids decrease was statistically significant. The albumin/globulin ratio shifted and serum glutamic-pyruvic-transaminase activity increased. Fat biopsies in females showed PCB isomer accumulation in adipose tissue. After 4 months, menstrual cycles were altered with duration of menses increasing or being absent. The conception rate in 5ppm PCB animals was decreased when compared to controls; six out of eight animals that conceived had three abortions, one resorption, one stillborn, and one normal birth. All females that received 2.5ppm PCB conceived but three had resorptions. Male animals had no gross breeding capabilities altered. The authors conclude that adult female monkeys have serious reproductive effects after PCB exposure. (Barsotti et al, 1976)

Study #3

reduced conception
increased fetal mortality

A group of 80 menstruating rhesus (Macaca mulatta) monkeys were randomly allocated to four similar test rooms (20 monkeys/room) and then randomly allocated within each room to one of five dose groups (four females/dose group/room). Each day, the monkeys self-ingested capsules containing doses of 0, 5, 20, 40 or 80 micrograms Aroclor 1254/kg body weight. After 25 months of continuous dosing, approximately 90% of the treated females had attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl (PCB) in their adipose tissue. Commencing on test month 37, each female was paired with an untreated male until either an impregnation occurred or the 29-month breeding phase of the study was completed. The females continued to receive their daily test dose during mating and gestation. To preclude an infant ingesting the mother's dosing capsule, dosing of the dam was discontinued when a nursing infant was approximately 7 wk old. Treatment was restarted when the infant was weaned at 22 wk of age. At parturition, and every 4 wk until weaning, milk and blood samples were obtained from the dam and a blood sample was obtained from the infant for PCB analysis. When the infant was 20 wk old, immunological testing was initiated and an adipose sample was obtained from the infant and dam for PCB analysis. Subsequently, further adipose and blood samples were obtained from the infant and blood specimens were obtained from the dam for PCB analysis. Concurrently, each infant was subjected to anthropometric measurements and detailed clinical examinations until it was approximately 122 wk old. At 122 wk some of the control and all of the treated infants were killed humanely and autopsied. A statistical analysis of the reproduction data provided evidence for a significant decreasing dose-related trend in conception rates and a significant increasing dose-related trend in foetal mortality. Several comparisons between impregnated and non-impregnated females did not implicate 'age' as a confounding factor regarding these results. The major findings with the infants involved some immunological test differences and mild clinical manifestations of PCB ingestion. (Arnold et al, 1995)

Study #4

dose-dependent effect on reproductive parameters
study used PCB commercial mixture Aroclor 1254

Groups of 16 female Macaca mulatta monkeys, whose average estimated age at study initiation was 11.1+/-4.1 years, self ingested capsules containing daily doses of 0, 5, 20, 40 or 80 ug of Aroclor 1254/kg bw for 2 years at which time 93% of the treated monkeys had attained a qualitative pharmacokinetic steady state. They were mated to untreated males while continuing to receive a daily dose of Aroclor 1254 during mating, gestation and the first 6 weeks of nursing. All infants were nursed for 22 weeks and then separated. The infants received no further PCB. Monitored parameters included daily health status; feed and water consumption; menstrual status (daily); body weight (weekly); hematology; serum chemistry; detailed clinical evaluation; PCB analysis of blood, adipose tissue and feces; T3/T4 levels (monthly); evaluation of estrogen and progesterone levels during one menstrual cycle just prior to breeding and immunological testing prior to and post breeding. Major treatment findings included: Reproduction - a dose dependent effect upon reproductive parameters; Immunology - several treatment related effects; PCB analysis - fecal analyses indicated greater than a 90% retention of the administered dose; Clinicals - changes to nail beds with subsequent nail loss, inflammation and dilatation of tarsal glands; Hematology - decreases in reticulocytes, mean platelet volume, hemoglobin, red blood cells; Serum biochemistry

decreases in cholesterol and total bilirubin; Infants - little effect on growth and development. (Arnold et al, 1991)

Study #5

prolonged menstrual and estrous cycles
reduced progesterone and estrogen
reduced ovulation

An overview of the industrial uses and adverse reproductive effects of polychlorinated biphenyls (PCB) in animals and humans is presented. A general formula is indicated, from which 209 PCB isomers are possible. In animal studies, placental transfer of PCB mixtures has been shown in mouse, rat, rabbit, and monkey, but only to a limited extent (less than 0.2 percent of the doses administered to the mothers are recovered in the fetuses). Transfer via the milk appears to be a more significant route to the offspring. In male mice, PCB mixtures reduce sperm counts and lower testicular and seminal vesicle weights at levels in the diet of 100 parts per million (ppm) and 400ppm, respectively. PCB at 5ppm prolongs the estrous cycle in monkeys and mice; reduces progesterone and estrogen levels in rats and monkeys, respectively; and reduces ovulation and prolongs the menstrual cycle in monkeys. In single generation studies, adverse effects on fertility have been observed only after massive intoxicating doses of PCB. Males appear more resistant than females. Some PCBs affect reproduction after continuous administration at nontoxic doses. The long term effects may be secondary to effects on hormonal balance. Prenatal exposure to PCB causes low birth weight, high perinatal and postnatal mortality, and low growth rate in several species of laboratory animal. The severity of the effects varies according to the type of PCB. Some PCBs, such as Aroclor-1221 (11104282), are mutagenic in the Ames test, while others are not. One study shows no effects on the rate of testicular DNA synthesis, and no increase is seen in the number of chromosomal aberrations in bone marrow cells or spermatogonia in another. Some evidence of carcinogenicity has been reported. Human studies have indicated that tissue levels of PCB are increasing in the world population. Thus, breast milk levels of PCB are routinely 100 parts per billion. Children born to PCB exposed women (Yusho disease) have a high mortality rate. PCB is considered carcinogenic, and the authors conclude that exposed women and their children should be studied more intensively. (Barlow et al, 1982)

Study #6

longer menstruation duration
progesterone levels were altered
study used PCB commercial mixture Aroclor 1254

Female rhesus monkeys (Macaca mulatta) ingested gelatin capsules containing daily doses of 0 (control), 5, 20, 40, or 80 mug of Aroclor 1254/kg/day (PCB) which was dissolved in corn oil plus glycerol. After approximately two years of dosing and when the monkeys were near an adipose tissue PCBs equilibrium, each dose group of 16 animals was randomly divided into two test groups. Daily blood samples from both groups were acquired for estrogen and progesterone analysis during one menstrual cycle. Test group 1 was sampled during February-March and test group 2 during August-September. Serum estrogen and progesterone concentrations in monkeys dosed with PCBs were equivalent to control values with the exception of the luteal phase progesterone levels in the 20 and 80 mug/kg/day dosed monkeys in test group 1. There was no difference in menstrual cycle length between control and treated monkeys for the month sampled, however, menses duration was marginally longer in the 80 mug/k (Truelove et al, 1990)

Study #7

reproductive problems
abnormal menses
infertility
increased abortion (miscarriage) rates
low birth weight offspring
fetal death
study used PCB commercial mixture Aroclor 1248

Data concerning the reproductive toxicity of polychlorinated-biphenyls (PCBs) were reviewed. Data have been obtained from animal experiments as well as the accumulated reports on the intoxications among humans through the accidental contamination of their environment with PCBs. Aroclor-1254 inhibited spermatogenesis in rodents. Clorphen-A60 demonstrated a lengthening effect on estrous cycles in mice. Rats demonstrated a significant reduction in plasma progesterone. PCBs with less than 48 percent chlorine have been associated with inherent estrogenic activity. Some PCBs may not have any significant estrogenic activity themselves, but may potentiate the effects of natural estrogens. Chronic dosing with Aroclor-1248 in the diet of rhesus-monkeys was lethal for some and among survivors caused various reproductive problems, including abnormal menses, infertility, increased abortion, and low birth weight of offspring. A number of animal species have demonstrated the placental transfer of PCBs. Rhesus-monkeys bred after exposure to Aroclor-1248 for six months demonstrated a high rate of abortion and fetal death. Reproductive effects among humans accidentally exposed to PCBs included overt abnormalities in the offspring, fetal loss, skin discoloration, dermal abnormalities, developmental deficits, behavioral problems, thick secretions from the eyes, cysts of the Meibomian glands, and edema of the eyelids and face. Exposure to neonates may occur through the breast milk of nursing mothers. (Lione, 1988)

Study #8

impaired breeding efficiency
abortions
stillbirths
high infant mortality

A spontaneous, progressive disease occurred in a large domestic breeding colony of rhesus monkeys (Macaca mulatta). The disease was characterized by slow but continuous weight loss, alopecia, acne, facial edema, diarrhea and trauma from other monkeys. Breeding efficiency was impaired with a high incidence of abortions and stillbirths. Live offspring were small and unthrifty contributing to a high infant mortality rate. The cause of this disease was polychlorinated biphenyls (PCSs) which were present in the concrete sealant on the cage floors. Removing the sealant and resurfacing the floors alleviated the problem. (Altman et al, 1979)

Study #9

reproductive effects are seen in monkeys at PCB levels of 0.12 mg/kg/day.

Sources and pathways in the environment: The estimated cumulative world production of PCBs since 1930 is of the order of I million tonnes. Of this, more than one-half has entered dumps and landfills, where it is likely to be stable and released only very slowly. Much of the remainder has entered the environment by the disposal of industrial fluids into rivers and coastal waters, by leakage from non-enclosed systems, or by volatilization into the atmosphere from incineration of PCB-containing material at dumps. The ultimate reservoirs of PCBs and PCTs that enter the environment are mainly sediments of rivers and coastal waters. PCBs and PCTs are stable in the environment, but a small proportion is transformed by biological action and possibly by photolysis. Concentration in the environment: Measured concentrations of PCBs in air range from 50 ng/m3 to less than 1 ng/m3. Non-polluted fresh waters should contain less than 0.5 ng of PCBs per litre compared with 50 ng per litre in moderately polluted rivers and estuaries, and 500 ng per litre in highly polluted rivers. Concentrations of PCB in sediments range from 0.006 in non-polluted areas to 61 mg/kg in highly polluted areas. The concentration in living organisms depends upon the extent of local pollution, the amount of fat in the tissues, and the trophic stage of the organism in food chains (biomagnification). Highest tissue levels were found in marine ecosystems with very high values in top predators from polluted areas (BCFs of up to 71 400 have been measured in fish), though most of the fish caught for human consumption contains PCBs at levels of less than 0.1 mg/kg in muscle tissue. There is no information available on the environmental distribution of PCTs. Metabolism: PCBs are well absorbed by mammals through the gastrointestinal tract, lungs, and skin. They are stored mainly in adipose tissue and there is some placental transfer. Excretion in mammals is mainly through faeces, where the PCBs appear as phenolic metabolites; they appear unchanged in human milk. In birds, there is a considerable excretion in eggs. The rate of excretion in faeces is dependent on the rate of metabolism and this is much influenced by the number and orientation of the chlorine substituents. As environmental PCBs pass up biological food chains, there is a progressive loss of the lower chlorinated components owing to selective biotransformation, and only traces of PCBs containing less than five chlorine atoms per molecule are found in human fat. The smaller amount of information available concerning the PCTs indicates that they also are absorbed from the gastrointestinal tract and undergo selective biotransformation, but that the concentration in fat in relation to that in other tissues appears to be less than is observed with the PCBs. The extent of human exposure: Surveys on human adipose tissue in several countries have shown that most samples contain levels of PCBs in the region of I mg/kg or less, although higher values have been reported from some countries. Much higher values, up to 700 mg/kg, have been found in fat from men occupationally exposed. Several national surveys give PCB concentrations in the blood in the region of 0.3 ug/l00 ml but levels approaching 200 ug/l00 ml have been measured in men occupationally exposed, and these may be associated with skin lesions. Most surveys on human milk have shown PCB concentrations in the region of 0.02 mg/litre, although concentrations up to 0.1 mg/litre have been recorded. Results from the very few investigations on PCT concentrations in fat and blood suggest that these may be equal to those of PCBs. An estimate of the total daily intake of PCBs in air, water, and diet by individuals not occupationally exposed indicates that this falls within the range of 5-100 ug, which may be supplemented by unknown amounts from non-dietary sources. This estimate has some support from measurements of concentrations in human milk. Experimental studies on the effects of PCBs and PCTs: Most of the studies on the toxicity of PCBs have been performed with the commercial mixtures. The PCBs are of low acute toxicity but the effects are cumulative with prolonged administration; in mammals, liver enlargement is observed that may progress to liver damage. Non-metastasizing neoplastic liver nodules have been produced in rats and mice, some of which were classified as hepatocellular carcinomas on the basis of histological criteria in one study in rats and one study in mice. The monkey is much more sensitive to PCBs than the rat, showing effects similar to those seen in human Yusho patients (See section 8, p 65) with a similar order of exposure. Low dose effects on fertility have been seen in both the monkey and the mink, a species that is also relatively sensitive to PCBs. Other effects of PCBs include porphyria, immunosuppression, and interference with steroid metabolism; some of these may be attributable to the increase in microsomal enzyme activity associated with liver enlargement. Some of the toxic effects can be attributed to impurities in the commercial products. The acute oral toxicity of Arochlors 1242 and 1254 is low for the mallard- duck, LD50s > 2 g/kg body weight. The toxicity of PCBs to fish is not high by comparison with that of some pesticides, but some aquatic invertebrates are more sensitive. The 96-h LC50 for adult fish was 1.17 mg/l for Arochlor 1221 and 60 mg/l for Arochlor 1260. Young fish appear to be more sensitive, 96-h LC50s was 15 and 8 ug/l respectively for Arochlors 1242 and 1254. The threshold for survival and reproduction of Daphnia magna exposed to Arochlor 1248 was 5 ug/l. There is little information on the toxicity of the PCTs. Clinical studies of the effects of PCBs in man: Information on the effects of PCBs in man has been obtained from a large-scale incident in Japan (Yusho), in which over 1000 individuals showed signs of poisoning from the ingestion of rice oil contaminated with PCBs from a heat exchanger liquid. The most striking effects were hypersecretion in the eyes, pigmentation and acneiform eruptions of the skin, and disturbances of the respiratory system. Babies born to Yusho mothers were of less than normal size and initially showed skin pigmentation. Over a six-year period, the effects on the skin diminished very gradually, but the nonspecific symptoms tended to become somewhat more prominent. The smallest dose of PCBs calculated to produce an effect was approximately 0.5 g over about 120 days, but as the rice oil contained chlorinated dibenzofurans at a concentration of 5 mg/kg of rice oil in addition to PCBs at 2000 3000 mg/kg it is not certain that the symptoms were due solely to PCBs. Dose-effect relationships: Experimental studies on the dose effect relationship have shown that no effects on growth, and reproduction are seen in rats receiving PCB levels of I mg/kg body weight per day; there may be liver enlargement and a reversible induction of microsome enzyme activity at a level of I mg/kg/day but not at 0.1 mg/kg/day. Effects on reproduction are seen in the monkey with PCB levels of about 0.12 mg/kg/day. Symptoms were reported in some Yusho (human) patients ingesting less than 0.1 mg/kg/day. (WHO, 1976)

References

Altman NH,,New AE, McConnell EE, Ferrell TL. A spontaneous outbreak of polychlorinated biphenyl (PCB) toxicity in rhesus monkeys (Macaca mulatta): clinical observations. Lab Anim Sci; VOL 29, ISS 5, 1979, P661-5

Arnold DL, Bryce F, Karpinski K, Mes J, Tryphonas H, Truelove J, Zawidzka ZZ. Toxicity of polychlorinated biphenyls (Aroclor 1254) in adult monkeys as a consequence of continuous exposure and in infant monkeys exposed during pregnancy and nursing. Toxicologist 1991 Feb;11(1):220. Author Address: Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Protection Branch, Ottawa, Ont.

Arnold DL, Bryce F, McGuire PF, Stapley R, Tanner JR, Wrenshall E, Mes J, Fernie S, Tryphonas H, Hayward S, et al. Toxicological consequences of aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys. Part 2. Reproduction and infant findings. Food Chem Toxicol 1995 Jun;33(6):457-74. Author Address: Toxicology Research Division, Health Canada, Ottawa, Ontario.

Barlow SM, Sullivan FM. Polychlorinated Biphenyls. Reproductive Hazards of Industrial Chemicals. An Evaluation of Animal and Human Data; London, Academic Press, pages 455-482, 58 references, 1982

Barsotti DA, Marlar RJ, Allen JR. Reproductive Dysfunction In Rhesus Monkeys Exposed To Low Levels Of Polychlorinated Biphenyls (Aroclor 1248). Food and Cosmetics Toxicology, Vol. 14, pages 99-103, 19 references, 1976.

Lione A. Polychlorinated Biphenyls and Reproduction. Reproductive Toxicology, Vol. 2, No. 2, pages 83-89, 48 references, 1988.

Muller WF, Hobson W, Fuller GB, Knauf W, Coulston F, Korte F. Endocrine Effects of Chlorinated Hydrocarbons in Rhesus Monkeys. Ecotoxicology and Environmental Safety, Vol. 2, No. 2, pages 161-172, 10 references, 1978

TRUELOVE JF, TANNER JR, LANGLOIS IA, STAPLEY RA, ARNOLD DL, MES JC. Effect of polychlorinated biphenyls on several endocrine reproductive parameters in the female rhesus monkey. ARCH ENVIRON CONTAM TOXICOL; 19 (6). 1990. 939-943. Author Address: Toxicol. Res. Div., Bureau Chem. Safety, Food Directorate, Health Protection Branch, Health Welfare Can., Ottawa, Ontario K1A OL2, Can.

World Health Organization (WHO) Working Group. Polychlorinated biphenyls and terphenyls. TA:Environmental Health Criteria PG:85 p YR:1976 IP: VI:2

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