Toxicity studies carcinogenicity testing

No review of subacute, subchronic, or chronic toxicity of chemical warfare nerve agents would be complete without discussion of the significant paper by Munro et al. that reviewed both animal and human studies of the nerve agents tabun (GA), sarin (GB), and VX. These studies included subacute, subchronic, and chronic toxicity studies in animals. Special attention was paid to the phenomenon of Organophosphorus-Induced Delayed Neuropathy (OPIDN). Reproductive toxicity and carcinogenicity tests were reviewed as well as in vitro studies of mutagenicity. Munro et al. s findings can be summarized as follows ... 

In additional EPA studies, subchronic inhalation was evaluated ia the rat for 4 and 13 weeks, respectively, and no adverse effects other than nasal irritation were noted. In the above-mentioned NTP chronic toxicity study ia mice, no chronic toxic effects other than those resulting from bronchial irritation were noted. There was no treatment-related increase ia tumors ia male mice, but female mice had a slight increase in bronchial tumors. Neither species had an increase in cancer. Naphthalene showed no biological activity in other chemical carcinogen tests, indicating Htde cancer risk (44). No incidents of chronic effects have been reported as a result of industrial exposure to naphthalene (28,41). 

By the time Phase III testing is completed, some additional preclinical safety tests must also generally be in hand. These include the three separate reproductive and developmental toxicity studies (Segments I and III in the rat, and Segment II in the rat and rabbit) and carcinogenicity studies in both rats and mice (unless the period of therapeutic usage is intended to be very short). Some assessment of genetic toxicity will also be expected. 

Cytogenetic effects were not found in bone marrow cells from mice treated with 1,4-dichlorobenzene by gavage at levels up to 1,800 mg/kg/day in a 13-week study (NTP 1987). No increase in micronucleated cells occurred even at levels that were extremely toxic to the test animals, resulting in liver toxicity and decreased survival rates. As noted by the authors of that study, the observed carcinogenic activity of... 

B.33 Combined chronic toxicity/carcinogenicity test B.43 Neurotoxicity study in rodents... 

OECD. 2002a. Guidance notes for analysis and evaluation of chronic toxicity and carcinogenicity studies. OECD Series on Testing and Assessment No. 35. Environment Directorate, Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology. ENV/JM/MONO(2002)19. Paris OECD. 

The National Toxicology Program performed a subchronic study of CN to generate data on the maximally tolerated dose (MTD) of this agent preparatory to launching a full-scale chronic-toxicity and carcinogenicity bioassay.38 The test was conducted in Fischer 344... 

Within the pasi few years, the costs of carrying out long-term hioassays have increased markedly tn the point at which it is loo cosily for small nr medium-size manufacturers to fund a study of the long-term toxicity or carcinogenicity of any chemicals proposed for commercial development. Therefore, many short-term tests are being developed lo predict which compounds would more likely be carcinogenic. A prominent one is... 

In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor affinities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species. 

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