Histopathology chronic toxicity studies

Chronic-Duration Exposure and Cancer. No information is available on the effects of chronic exposure to 1,1-dichloroethane in humans. The NCI study reported histopathological examinations for endpoints of systemic toxicity in addition to the neoplastic effects in rats and mice. No MRL can be derived for long-term exposure. Additional chronic toxicity studies particularly by the inhalation route would be useful to fully assess potential human health hazard from long-term exposure to... 

Acute toxicity studies in two animal species are required by the FDA for all new drugs prior to their use in humans. Subacute and chronic toxicity studies are required for drugs that are intended for chronic systemic use. Toxicity testing in animals usually involves the determination of lethal dose, monitoring of blood, hepatic, renal, and respiratory functions, gross and histopathologic examination of tissues, and tests of reproductive effects and potential carcinogenicity. 

Neurotoxicity. No histopathological effects on organs and tissues of the neurological systems of animals were found in subchronic and chronic oral studies, but signs of central nervous system toxicity were reported in inhalation, oral, and dermal studies. A battery of tests for neurotoxicity would provide further information of the neurotoxicity in animals, which then might be related to possible neurotoxic effects in humans. 

Toxicity studies consist of acute, subacute, and chronic phases, which come under preclinical evaluation in species to asses the extent of toxicity by using various parameters (e.g., hematology, biochemical, histopathologic, body weight, food intake, water intake, general behavior). General requirements of a toxicity study are given in Appendixes I and II. 

Dose selection for subchronic and chronic toxicology studies should be based on the results from acute toxicity studies and pharmacokinetic evaluations. The three typical dose levels are (a) a no-toxic-effect level, which should be at least equivalent to, and hopefully a multiple of, the proposed human dose, (b) a dose level that produces a toxic effect in clinical observations, clinical pathology, or histopathologic changes, and (c) a dose level between these two. 

Preclinical toxicology studies should address the standard systemic and local reactogenicity, histopathology, and toxicity (acute and chronic dosage) in rodent and nonrodent animals. Since the FDA and some European authorities decided to classify mRNA-based therapies as no-gene therapy (for nonreplicative mRNA as depicted in this chapter), the implementation of clinical trials does not require additional specific toxicology testing. 

In a second experiment (Hanhijarvi, Nevalainen, and Mannisto, 1985), the chronic, cumulative dermal effects of anthralin chemicals were studied in minipigs. Using only 12 animals, they were able, by having 32 sites per animal, to study the effects of two different chemicals (dithranol and butantrone both anthralins) in three different formulations at three different concentrations each. The protocol also included observations for systemic toxicity, clinical laboratory measurements, plasma drug analyses, and gross and histopathological examinations. 

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