Renate D. Kimbrough

THE TOXICITY OF POLYCHLORINATED POLYCYCLIC COMPOUNDS AND RELATED CHEMICALS

(1973). The Toxicity of Polychlorinated Polycyclic Compounds and Related Chemicals. CRC Critical Reviews in Toxicology: Vol. 2, No. 4, pp. 445-498.

Polychlorinated Biphenyls (PCBs) and Human Health: An Update

Polychlorinated biphenyls (PCBs) are a mixture of 209 different chlorinated biphenyl congeners (forms) of which 36 are environmentally relevant. PCBs are lipid (fat)-soluble, stable compounds. PCBs may be contaminated with more highly toxic polychlorinated dibenzofurans (PCDFs). Some PCDFs were primarily responsible for the two poisoning outbreaks--Yusho and Yu-Cheng. Based on the reports on workers and the general population, no clear and convincing evidence that PCB exposures were casually associated with adverse health effects was advanced; this included cancer for a wide range of body burdens and exposures for serum PCB concentrations > 1000 ppb (micrograms/l) and adipose PCB levels > 400 ppm (mg/kg). No meaningful reproductive problems have been identified in female capacitor workers. In the opinion of the review author, the available evidence for cancer and for reproductive effects is inconclusive. Adverse neurobehavioral effects in infants and young children have been reported in a study of women in the general population and a study of fish eaters and their offspring. The adverse effects observed in the two studies were not the same; the exposure assessments in both studies are not well defined and have many uncertainties. Subhuman primates appear to be more sensitive to reproductive and other adverse effects of PCBs than humans. Obvious external clinical signs are observed in the offspring of subhuman primates at dosage levels below those experienced by female capacitor workers and members of the general population prior to the control of PCBs.

The Pbb Episode in Michigan: An Overall Appraisal

Polybrominated biphenyls (PBB) were used as a fire retardant. In common with other halogenated hydrocarbons, PBBs are lipophilic and resistant to chemical and metabolic degradation. Cattle on about 25 Michigan farms were exposed to as much as 250 g per head of PBB when it was accidentally mixed in cattle feed in 1973 to 1974. Livestock exposures several orders of magnitude lower occurred on several hundred other farms because of carryover and equipment contamination in feed mills. Approximately 85% of the Michigan population received some exposure to PBB because dairy product marketing involves mixing milk from many farms. A few cases of high human exposure, which may have been as great as 10 g, occurred when residents of the more highly exposed farms consumed their own products. Although numerous clinical signs and pathological changes were reported in exposed cattle, only anorexia, lacrimation, emaciation, hyperkeratosis, and kidney damage were confirmed in controlled studies. The acute toxicity of PBB in laboratory animals is low, but a variety of subacute effects have been reported. Induction of microsomal enzymes, enlargement and histopathological changes of the liver, fetotoxicity, and immunosuppression are among the more significant. Epidemiological studies of exposed humans have revealed no pattern ofmorexa0» clinical signs or symptoms that were related to PBB exposure. A complete evaluation of the human consequences of exposure to PBB await the conclusion of long-term epidemiological studies. 84 references.«xa0lessPolybrominated biphenyls (PBB) were used as a fire retardant. In common with other halogenated hydrocarbons, PBBs are lipophilic and resistant to chemical and metabolic degradation. Cattle on about 25 Michigan farms were exposed to as much as 250 g per head of PBB when it was accidentally mixed in cattle feed in 1973 to 1974. Livestock exposures several orders of magnitude lower occurred on several hundred other farms because of carryover and equipment contamination in feed mills. Approximately 85% of the Michigan population received some exposure to PBB because dairy product marketing involves mixing milk from many farms. A few cases of high human exposure, which may have been as great as 10 g, occurred when residents of the more highly exposed farms consumed their own products. Although numerous clinical signs and pathological changes were reported in exposed cattle, only anorexia, lacrimation, emaciation, hyperkeratosis, and kidney damage were confirmed in controlled studies. The acute toxicity of PBB in laboratory animals is low, but a variety of subacute effects have been reported. Induction of microsomal enzymes, enlargement and histopathological changes of the liver, fetotoxicity, and immunosuppression are among the more significant. Epidemiological studies of exposed humans have revealed no pattern of clinical signs or symptoms that were related to PBB exposure. A complete evaluation of the human consequences of exposure to PBB await the conclusion of long-term epidemiological studies.

Weight of evidence evaluation of potential human cancer risks from exposure to polychlorinated biphenyls: An update based on studies published since 2003

Drawing on all data available in 2003, the WoE of the human epidemiological data for polychlorinated biphenyls (PCBs) demonstrates that exposure to a mixture of PCBs (i.e. Aroclors) did not pose a cancer risk to humans (. This evaluation was based on criteria established by the US Environmental Protection Agency (EPA) as well as on a different methodology used by the Agency for Toxic Substances and Disease Registry (ATSDR). Subsequently, at least 15 more studies on the potential cancer risks (both incidence and mortality) of PCBs have been published. All studies published since 2003 are critically reviewed using the criteria established by the and . None of the studies published since 2003 change the conclusions drawn by : “that the weight of evidence does not support a causal association for PCBs and human cancer”. This conclusion pertains to all cancers combined, as well as to the various cancers that have been sporadically reported in the occupational cohort mortality studies. With respect to breast cancer risk, the WoE is compelling that environmental exposure to PCBs is not etiologically implicated in breast-cancer risk. This conclusion is supported by the consistently negative findings for increased breast-cancer mortality in occupational studies, which now involve almost 9,000 women occupationally exposed to PCBs. Similarly, the incidence studies in which PCB background levels are reported to be associated with increased risk of non-Hodgkins lymphoma or prostate, testicular, and intestinal cancer are not corroborated by occupational cohort studies with PCB exposures far in excess of environmental exposures. The most likely explanation for these discordant findings is discussed in this review. Finally, the recent elucidation of the mode of action by which PCBs promote liver tumors in rats, combined with the demonstration that none of the key events in the mode of action occurred until substantial tissue accumulation of total PCBs had occurred, casts further doubt that PCB exposure at environmental or occupational levels poses a carcinogenic risk to humans. The dramatic differences between rodents and humans in sensitivity to PCB-mediated induction of CYP1A1 suggests that even occupational exposures to PCBs have never resulted in PCB body burdens approaching the levels required to initiate the sequence of events involved in the promotion of liver tumors in rodents.

The effect of technical and purified pentachlorophenol on the rat liver.

Abstract Dietary concentrations of 0, 20, 100, and 500 ppm of technical grade pentachlorophenol were fed to male and female Sherman strain rats for 8 months. The same experiment using purified pentachlorophenol was carried out. The food consumption was measured in all rats during the second week of exposure and for one week every 6 weeks thereafter. An autopsy was performed on all rats at the end of the experiment. The brain, lungs, spleen, liver, kidneys, heart, and testes were weighed and examined grossly and microscopically in all rats fed purified pentachlorophenol, all female rats fed technical pentachlorophenol, and in the male rats fed the highest dose of technical pentachlorophenol and the controls. Only the kidneys and livers were examined microscopically in the male rats fed 20 and 100 ppm of technical pentachlorophenol. Although the food intake was comparable, male and female rats fed 500 ppm of technical and male rats fed 500 ppm of purified pentachlorophenol gained less weight. The livers of the male and female rats fed 500 ppm technical pentachlorophenol weighed significantly more than those of the controls. The kidneys of all male rats fed purified pentachlorophenol weighed significantly more than those of the controls; however, there was no dose-related increase. No morphological changes were seen in the kidneys. At the 500-ppm dietary concentrations, technical pentachlorophenol produced a severe effect in the liver of female rats characterized by vacuolation of the hepatocytes, an increase in fibroblasts and other mononuclear cells within sinusoids, bile duct proliferation, periportal fibrosis, degenerated liver cells, increased mitotic figures, and an accumulation of brown pigment in macrophages and in Kupffer cells. In male rats at the 100- or 500-ppm dietary concentrations of technical pentachlorophenol, the predominant lesion consisted of enlarged pleomorphic hepatocytes which had foamy cytoplasm or cytoplasm with large vacuoles. The walls of the hepatic central veins of the livers in animals of both sexes were thickened. At the 100-ppm dietary concentrations similar but less pronounced effects were observed in the livers. Only mild alterations were noted at the 20-ppm dietary concentration. Purified pentachlorophenol caused slightly enlarged liver cells with occasional eosinophilic cytoplasmic inclusions at 500 ppm but no alterations were observed in the livers of rats fed the 100- and 20-ppm dietary concentrations. The results suggest that most of the toxicity associated with feeding technical grade pentachlorophenol to rats at these dietary concentrations stems from toxic contaminants rather than from pentachlorophenol.

A Fatal Episode of Accidental Methomyl Poisoning

Three fatalities from the accidental ingestion of methomyl, a carbamate pesticide, are reported. The methomyl had been stored in an unlabeled tin can and was accidentally used in preparing roti, an Indian dish. The identification of the source of the poison through animal tests and further chemical identification is described. The lethal dose of methomyl was estimated to have been between 12 and 15 mg/kg body weight.

Short-term chlordecone toxicity in rats including effects on reproduction, pathological organ changes, and their reversibility☆

Abstract Chlordecone was fed to male and female adult Sherman strain rats at concentrations of 0 and 25 ppm for 3 months. Following this, all rats were fed control diet for 4.5 months. During this recovery period they were bred twice. Immediately after exposure was discontinued, reproduction in the females was completely inhibited; this was coupled with hyperplasia of the adrenal cortex. Two months after exposure was discontinued, reproductive ability was partially restored. Reproduction in males was not affected at any time at this dose. Following the 4.5-month recovery period, the adrenals in the previously exposed females had returned to normal size; however, their livers were still enlarged and continued to show some morphologic changes. Although the experimental rats gained less weight during exposure than the controls, the body weights of control and experimental rats following the 4.5 month recovery period were the same.

The effect of different diets or mineral oil on liver pathology and polybrominated biphenyl concentration in tissues

Abstract Groups of 10 adult (3.5 months) male Sherman strain rats were given 0 or a single dose of 500 mg polybrominated biphenyls (PBB) in corn oil/kg by stomach tube. Three weeks later, groups of 10 rats each that had received 500 mg/kg and groups of 10 rats each that had been given corn oil were started on a purified 20% fiber or 4% fiber diet. Ten rats each that had received 500 mg/kg or corn oil were continued on Purina Chow. An additional group of 10 rats given 500 mg/kg was also continued on Purina Chow but was given 2 ml mineral oil/kg three times a week. All rats were given the different diets or the mineral oil for 3 months. Chemical analysis of blood, liver, and adipose tissue by gas chromatography for PBBs showed no statistically significant difference in the PBB concentrations in blood and adipose tissue among the different groups. The PBB concentrations in the liver of rats fed Purina Chow were significantly lower than in the other groups if they were calculated on a wet weight basis. When PBB concentrations in liver were calculated on a lipid basis, the differences were not statistically significant. Total liver lipids showed statistically significant increases in rats given 500 mg/kg followed by 4 or 20% purified fiber diet or by Purina Chow and 2 ml of mineral oil/kg every other day. Microscopic examination of the livers showed essentially normal parenchyma in all rats that had not received PBBs. The rats given a single oral dose of 500 mg/kg which was followed by Purina Chow or Purina Chow and mineral oil showed some centrolobular vacuolated hepatocytes and enlarged hepatocytes around the central veins. The vacuolation was more pronounced in rats receiving Purina Chow and mineral oil also. Rats given 500 mg/kg followed by 4 or 20% purified fiber diet showed severe steatosis of the liver with megalo-hepatocytes, areas of cell necrosis and interstitial fibrosis. The interstitial fibrosis was more pronounced in rats given the 20% purified fiber diet. These results indicate a pronounced additive effect on PBB liver toxicity in rats by the 4 or 20% purified fiber diets which may be deficient in some nutrients or may prevent absorption of important nutrients.

Subchronic inhalation toxicity of isobutyl nitrite in BALB/c mice. I. Systemic toxicity.

The effects of subchronic inhalation exposure to isobutyl nitrite (IBN) on body weight, selected organ weights, hematology, and gross pathology and histopathology of BALB/c mice were evaluated. Mice of both sexes were exposed at 0, 20, 50, or 300 ppm IBN for 6.5 h/d, 5 d/wk for up to 18 wk. Most changes in measured indices occurred in mice exposed at 300 ppm IBN and included decreased thymus weight (females); decreased liver weight (males); decreased white blood cell counts (males); mild focal hyperplasia and vacuolization of the epithelium lining bronchi and bronchioles of the lungs (males and females). Organ weight and hematologic changes, however, were not accompanied by any observed histologic changes. In addition, elevated methemoglobin concentrations were detected in mice of both sexes exposed at 50 and 300 ppm IBN. Body weights were not adversely affected by exposure. These data suggest that mild tissue injury, restricted to the lung, and methemoglobinemia are the major toxic effects observed following exposures of mice to IBN at concentrations up to 300 ppm for 18 wk. No treatment-related effects were noted in mice exposed at 20 or 50 ppm IBN, except for slight elevations in methemoglobin concentrations in mice exposed at 50 ppm.

Aflatoxin and Reye's Syndrome: A Study of Livers from Deceased Cases

In order to reinvestigate a strong reported association, we attempted to identify aflatoxin in the livers of 12 children who presumably died of Reyes Syndrome and in the liver of one child who died accidentally. Aflatoxins were detected, but not confirmed in only one of the liver specimens (limits of detection 20 ppt). In addition, the microscopic appearance of the livers was reviewed. Although most of the cases fit the clinical definition of Reyes Syndrome, the microscopic appearance of the liver was varied. We conclude that aflatoxin is not regularly recoverable from cases of Reyes Syndrome at a high rate, and question the proposed etiologic relationship. We confirm the varied appearance of the liver late in the course of Reyes Syndrome; however, microvesicular fat was present in most cases.