Identifying toxicity laboratory studies

Few neurological toxicities after inhalation exposures to HDl could be identified in laboratory animals. In an acute-duration study, groups of 4 male albino ChR-CD rats were exposed to various concentrations of HDl for 4 or 8 hours. When rats were exposed to 370 ppm from a bubbler of HDl warmed to 40-50 °C, they died after 2-3 hours of exposure, with irritation and convulsions observed prior to death. However, mechanical difficulties with the exposure apparatus may have contributed other factors that might have been responsible for the convulsions and eventual death of these animals (Haskell Laboratory 1961). 

There are no human data from which to develop a quantitative evaluation. One laboratory study in rats identified a NOAEL of 1,000 mg/kg for developmental effects. Using an aggregate uncertainty factor of 1,000 (10 for interindividual variation, 10 for extrapolation from rats to humans, 10 for an incomplete data set), the UEL for developmental toxicity for a short term exposure is 1 mg/kg/d. 

A similar UEL is calculated for chronic exposures. Laboratory studies in rats identified a NOAEL of 10,000 ppm based on a significant increase in the incidence of Leydig cell hyperplasia. Applying an aggregate uncertainty factor of 300 (3 for interspecies extrapolation, 10 for intraindividual differences, and 10 for an incomplete database), the UEL for reproductive and developmental toxicity for a chronic exposure is 33.3 ppm. 

Epidemiology studies are, of course, useful only after human exposure has occurred. For certain classes of toxic agents, carcinogens being the most notable, exposure may have to take place for several decades before the effect, if it exists, is observable - some adverse effects, such as cancers, require many years to develop. The obvious point is that epidemiology studies can not be used to identify toxic properties prior to the introduction of a chemical into commerce. This is one reason toxicologists turn to the laboratory. 

Toxic properties are identified in three basic ways through case reports with the tools of epidemiology, and through laboratory studies, typically involving animals but also involving micro-... 

Within the United States of America alone, some 20 million animals (1984 data) were used for a variety of laboratory studies, biomedical and behavioural research, toxicity testing, education, and for various monitCHing requirements. Public intoiest in animal welfare has instigated academic and emotional debates over many of these uses of animals. Stimulated by this concern thrae has been an efrmt to identify, refine, and validate non-animal alternatives for research, product safety testing, and monitoring [22]. 

The toxicological characteristics of substances intended to be administered to humans, or which might be added to the food chain or which may pollute the environment, are studied in animals in order to assist in predicting safety in humans. It should be understood that this goal is not always achieved. Frequently, adverse effects occur in humans that were not first identified in animal studies, and toxicities observed in laboratory animals do not always have their counterpart in humans. The reasons for predictive failures are varied and it is not appropriate to discuss them here the interested reader can find many excellent reviews of the subject (Balazs, 1976 Rail, 1979 Garattini, 1982). However, as will be demonstrated in the remainder of this chapter, almost all of the adverse side effects described thus far in laboratory animals have been reported to occur in humans. 

Note Proposals were based on observations of at-risk human populations, e.g., chimney sweeps in London. Decades typically passed before definitive proof of cancer causation was provided by laboratory studies. In the past half century there have been inaeased efforts to identify carcinogenic agents proactively by means of chronic toxicity testing in rodents (Chapter 5). 

Polychlorinated dibenzofurans (PCDFs) are the major identified toxic contaminants in Aroclors and Japanese Kaneclors, whereas European PCB products contain PCDFs and heptachloronaphthalenes as contaminants (Vos etal, 1970). Laboratory studies have indicated the possibility of photochemical formations of CDFs and PCDFs as secondary products in commercial PCB mixtures (Roberts etaL, 1978). However, the effect of industrial use and environmental aging upon the concentration of PCDFs in commercial PCBs has not been studied. 

So far, we have discussed various aspects of toxicology. This discipline identifies the manner in which chemicals exert toxicity, and the potency of chemicals of various species. The majority of toxicology studies are conducted under controlled conditions in the laboratory. This is necessary to establish cause and effect relationships and to develop dose-response information on specific chemicals. However, as discussed in the last chapter, humans are not typically exposed to concentrations tested in these laboratory studies. We learned about the uncertainty in trying to extrapolate toxicity information to humans or other species. In spite of this uncertainty, we are ultimately concerned with the potential impact of chemicals released into the environment. This issue concerns all of us because of the myriad ways we might interact with these chemicals. They can be present in our water, air, soil, or food. Estimating the likelihood of toxicity from exposure to chemicals in the environment is the focus of the discipline of risk assessment. 

For example, assume that a pond is contaminated with metals. One goal of the ecological risk assessment is to identify if a known sensitive aquatic species (e.g., freshwater shrimp) is impacted by the concentrations of metals in the pond. This shrimp is a source of food for predatory fish in the pond, and therefore its abundance is linked to the health of the community. Literature values could be used to identify safe concentrations of metals for various species, but not for the specific one of interest at our site. These could be used and extrapolated to the target species, which introduces uncertainty into the results. Alternatively, water and/or sediment from the site could be brought into the laboratory and the species of interest could be directly tested for toxicity. These studies are known as bioassays. Results of bioassays are used to develop a protective concentration relevant to the species and site of interest. 

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