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Chapter: Basic & Clinical Pharmacology : Introduction to Toxicology: Occupational & Environmental

Environmental Pollutants - Specific Chemicals

The polychlorinated biphenyls (PCBs, coplanar biphenyls) have been used in a large variety of applications as dielectric and heat trans-fer fluids, lubricating oils, plasticizers, wax extenders, and flame retardants.

ENVIRONMENTAL POLLUTANTS

Polychlorinated Biphenyls

The polychlorinated biphenyls (PCBs, coplanar biphenyls) have been used in a large variety of applications as dielectric and heat trans-fer fluids, lubricating oils, plasticizers, wax extenders, and flame retardants. Unfortunately, PCBs persist in the environment. Their industrial use and manufacture in the USA were terminated by 1977. The products used commercially were actually mixtures of PCB iso-mers and homologs containing 12–68% chlorine. These chemicals are highly stable and highly lipophilic, poorly metabolized, and very resistant to environmental degradation; they bioaccumulate in food chains. Food is the major source of PCB residues in humans.

A serious exposure to PCBs—lasting several months—occurred in Japan in 1968 as a result of cooking oil contamination with PCB-containing transfer medium (Yusho disease). Possible effects on the fetus and on the development of the offspring of poisonedwomen were reported. It is now known that the contaminated cooking oil contained not only PCBs but also polychlorinated dibenzofurans (PCDFs) and polychlorinated quaterphenyls (PCQs). Consequently, the effects that were initially attributed to the presence of PCBs are now thought to have been caused by a mixture of contaminants. Workers occupationally exposed to PCBs have exhibited the following clinical signs: dermatologic problems (chloracne, folliculitis, erythema, dryness, rash, hyper-keratosis, hyperpigmentation), some hepatic involvement, and elevated plasma triglycerides.

The effects of PCBs alone on reproduction and development, as well as their carcinogenic effects, have yet to be established in humans—whether workers or the general population—even though some subjects have been exposed to very high levels of PCBs. Repeated epidemiologic studies have found some increases in various cancers including melanoma, breast, pancreatic, and thyroid cancers, but the small number of cases and uncertain exposure status have left the carcinogenicity question unclear. In 1977, the IARC recommended that PCBs be regarded as likely carcinogenic to man, although the evidence for this classification was lacking. Some adverse behavioral effects in infants have been reported. An association between prenatal exposure to PCBs and deficits in childhood intellectual function was described for chil-dren born to mothers who had eaten large quantities of contami-nated fish. The polychlorinated dibenzo-p-dioxins (PCDDs), or dioxins, have been mentioned as a group of congeners of which the most important is 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD).In addition, there is a larger group of dioxin-like com-pounds, including certain polychlorinated dibenzofurans(PCDFs) and coplanar biphenyls. While PCBs were used com-mercially, PCDDs and PCDFs are unwanted byproducts that appear in the environment and in manufactured products as con-taminants because of improperly controlled combustion processes. PCDD and PCDF contamination of the global environment is considered to represent a contemporary problem produced by human activities. Like PCBs, these chemicals are very stable and highly lipophilic. They are poorly metabolized and very resistant to environmental degradation.

In laboratory animals, TCDD administered in suitable doses has produced a wide variety of toxic effects, including a wasting syndrome (severe weight loss accompanied by reduction of muscle mass and adipose tissue), thymic atrophy, epidermal changes, hepatotoxicity, immunotoxicity, effects on reproduction and development, teratogenicity, and carcinogenicity. The effects observed in workers involved in the manufacture of 2,4,5-T (and therefore presumably exposed to TCDD) consisted of contact dermatitis and chloracne. In severely TCDD-intoxicated patients, discrete chloracne may be the only manifestation.

The presence of TCDD in 2,4,5-T is believed to be largely responsible for other human toxicities associated with the herbi-cide. There is epidemiologic evidence indicating an association between occupational exposure to the phenoxy herbicides and an excess incidence of non-Hodgkin’s lymphoma. The TCDD con-taminant in these herbicides seems to play a role in a number of cancers such as soft tissue sarcomas, lung cancer, Hodgkin’s lym-phomas, and others.

Endocrine Disruptors

The potential hazardous effects of some chemicals in the envi-ronment are receiving considerable attention because of their estrogen-like or antiandrogenic properties. Compounds that affect thyroid function are also of concern. Since 1998, the pro-cess of prioritization, screening, and testing of chemicals for such actions has been undergoing worldwide development. These chemicals mimic, enhance, or inhibit a hormonal action. They include a number of plant constituents (phytoestrogens) and some mycoestrogens as well as industrial chemicals, particularly persistent organochlorine agents such as DDT and PCBs. Some brominated flame retardants are now being investigated as pos-sible endocrine disrupters. Concerns exist because of their increasing contamination of the environment, the appearance of bioaccumulation, and their potential for toxicity. In vitro assays alone are unreliable for regulatory purposes, and animal studies are considered indispensable. Modified endocrine responses in some reptiles and marine invertebrates have been observed. In humans, however, a causal relation between exposure to a spe-cific environmental agent and an adverse health effect due to endocrine modulation has not been established. Epidemiologic studies of populations exposed to higher concentrations of endo-crine disrupting environmental chemicals are underway. There are indications that breast and other reproductive cancers are increased in these patients. Prudence dictates that exposure to environmental chemicals that disrupt endocrine function should be reduced.

Asbestos

Asbestos in many of its forms has been widely used in industry for over 100 years. All forms of asbestos that have been used in industry have been shown to cause progressive lung disease that is characterized by a fibrotic process. Higher levels of exposure produce the process called asbestosis. Lung damage develops even at low concentrations of shorter fibers, whereas higher con-centrations of longer fibers are required to cause lung damage. Every form of asbestos, including chrysotile asbestos, causes an increase in lung cancer. Lung cancer occurs in people exposed at fiber concentrations well below concentrations that produce asbestosis. Cigarette smoking and exposure to radon daughters increase the incidence of asbestos-caused lung cancer in a syner-gistic fashion.

All forms of asbestos also cause mesothelioma of the pleura or peritoneum at very low doses. Other cancers including colon can-cer, laryngeal cancer, stomach cancer, and perhaps even lymphoma are increased in asbestos-exposed patients. The mechanism for asbestos-caused cancer is not yet delineated. Arguments that chrysotile asbestos does not cause mesothelioma are contradicted by many epidemiologic studies of worker populations. Recognition that all forms of asbestos are dangerous and carcinogenic has led many countries to ban all uses of asbestos. Countries such as Canada, Zimbabwe, and others that still produce asbestos argue that asbestos can be used safely with careful workplace environ-mental controls. However, studies of industrial practice make the “safe use” of asbestos highly improbable.


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