Bioassay data, animal

Guilmette RA, Eidson AF. 1992. Using animal dosimetry models to interpret human bioassay data for actinide exposures. J Radioanal Nucl Chem 156(2) 425-449. 

Cancer. No studies were found regarding the carcinogenicity of chlorobenzene in humans. In a chronic bioassay in animals, chlorobenzene (up to 120 mg/kg/day) did not produce increased tumor incidences in mice of both sexes or in female rats (NTP 1985). It was noted, however, that male rats showed a statistically significant increase in neoplastic nodules at the highest dose level tested. While there is strong evidence for neoplastic nodules, existing data are inadequate to characterize the potential for chlorobenzene to cause cancer in humans and animals. 

In practice, animal bioassay data are generally the primary data used in risk assessments. Animal studies are well-controlled with known exposures, and they are carried out with detailed, careful clinical and pathological examinations. The use of laboratory animals to determine potential toxic effects in humans is a necessary and accepted procedure. It is a recognized fact that effects in laboratory animals are usually similar to those observed in humans at comparable dose levels. Exceptions are primarily attributable to differences in the pharmacokinetics and metabolism of the xenobiotics. 

Cancer risk assessment involves two steps. The first step is a qualitative evaluation of all epidemiology studies, animal bioassay data, and biological activity (e.g., mutagenicity). The substance is classified as to the carcinogenic risk to humans based on the weight of evidence. If the evidence is sufficient, the substance may be classified as a definite, probable, or possible human carcinogen. 

The evaluation of the carcinogenic potential of a chemical exposure in humans must be based on analyses of all relevant data. Human epidemiologic and cfinical smdies, as well as accidental-exposure reports are considered and used to evaluate the carcinogenic potential of a substance. In the absence of human data, long-term bioassay data from controlled animal studies are used to derive theoretical excess carcinogenic risk estimates for exposed humans. The selection of data for estimating risk is based on the species and strain considered to resemble the human response most closely to provide the most accurate estimates. 

A Weight-of-Evidence (WOE) Method To provide further guidance on the evaluation of chemical interactions and their impact on risk values calculated from data not reflective of the mixture, a weight-of-evidence (WOE) method was developed [25,26], The assessment of WOE for interactions enables assessors to judge if the interactions influence the overall toxicity of the mixture and if the anticipated joint toxicity will be greater than or less than expected based on the principle of additivity. The WOE method yields a composite representation of all the evidence on toxicologic interactions from human studies to animal bioassay data relevance of route, duration, and sequence and the significance of interactions. The method consists of a classification... 

Hazard identification as determined from an adequate assessment of data from chronic/cancer bioassays in animals has been reviewed in Maronpot (1994), Health... 

In order to illustrate the various possible approaches to estimating a combined potency for a multisite carcinogen, an example is offered here. The carcinogen selected, 1,3-butadiene, is an important industrial chemical and a widespread air pollutant. Risk assessments for this chemical have been published (OEHHA 1992 US EPA 2002). The more recent estimate by US EPA (2002) depends primarily on estimates of risk from the various human epidemiology studies of industrial exposures to this chemical, but it is their analysis of the animal bioassay data and also that by OEHHA (1992) which are of interest for the present purpose. 

For several years, it has been acknowledged that whenever possible bioassay data should be corrected for early death. In both CDC s and EPA s analysis of Kociba et al (6), the individual animal pathology results were not available. Recently, these data were made available and the analysis showed some interesting results (76-77). The nonparametric Kaplan-Meier estimates of the probability of a female rat developing a hepatocellular neoplastic nodule or carcinoma by the end of 25 months, the duration of the Kociba study, are shown in Figure 5. These estimates are computed separately for each dose level and take into account the observation times of each rat. The values of these estimates for the two highest dose levels are 0.81 at... 

In their list of 43 tumorigenic agents in tobacco and/or smoke, Hoffmann and Hecht (1727) included the following volatile NNAs NDMA, NDEA, NEMA, and NPYR. Little comment was made about these four volatile NNAs and their supposed tumorigenicity to smokers. However, they did note that lARC (1870) had evaluated the bioassay data from laboratory animals exposed to these NNAs and considered the data sufficient to classify all four as tumorigenic to animals. lARC did not express an opinion as to whether these four were tumorigenic to humans. 

Inhalation and oral bioassays using rats and mice have been conducted (NCI 1977 NTP 1986). These data provide sufficient evidence to conclude that tetrachloroethylene is carcinogenic in animals. However, the oral study (NCI 1977) was limited by control groups smaller than treatment groups, decreased survival, and dose adjustments during the study. A dermal study conducted in mice reported no incidence of cancer in the test animals (Van Duuren et al. 1979). No additional cancer bioassays in animals appear to be necessary at this time. However, additional studies that clarify the relationship between peroxisome proliferation and hepatic cancers in mice as well as the relevance of hepatic glutathione conjugation of tetrachloroethylene to hiunans would be useful. 

Animal and Human Toxicity. The acute toxicity of lindane depends on the age, sex, and animal species, and on the route of adrninistration. The oral LD q in mice, rats, and guinea pigs is 86, 125—230, and 100—127 mg/kg, respectively. In contrast, most of the other isomers were considerably more toxic (94,95). Some of the other toxic responses caused by lindane in laboratory animals include hepato- and nephotoxicity, reproductive and embryotoxicity, mutagenicity in some short-term in vitro bioassays, and carcinogenicity (80). The mechanism of the lindane-induced response is not known. Only minimal data are available on the mammalian toxicides of hexachlorocyclopentadiene. 

No studies were located regarding cancer in humans after oral exposure to endosulfan. Carcinogenic effects of endosulfan were investigated in a number of chronic animal bioassays with rats and mice the available data provide no evidence that endosulfan is carcinogenic. 

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