Toxicity studies, conduct protocols

Common Study Protocols. The dog is the most commonly used nonrodent species in safety assessment testing (i.e., acute, subchronic, and chronic studies). The exception to this is its use in developmental toxicity and reproductive studies. For developmental toxicity studies, the dog does not appear to be as sensitive an indicator of teratogens as other nonrodent species such as the monkey (Earl et al., 1973) or the ferret (Gulamhusein et al., 1980), and, for reproductive studies, the dog is not the species of choice because fertility testing is difficult to conduct (due to prolonged anestrus and the unpredictability of the onset of proestrus) and there is no reliable procedure for induction of estrus or ovulation. 

U.S. EPA (1991) derived a cancer inhalation unit risk for sulfur mustard based on the results of inhalation animal studies conducted by McNamara et al. (1975, see Section 3.7.2) however, it was emphasized in the EPA report that the studies of McNamara et al. (1975) contained deficiencies which made a quantitative analysis difficult. Conducted in 1970, the studies do not conform to the modem norms of acceptable experimental protocol, and it is likely that there was bias in the assignment of the animals to the test categories (U.S. EPA, 1991). In addition, many of the exposures were very brief, included only a few animals, and many of the animals were sacrificed (and some were replaced) before their capacity to develop late-appearing tumors was fully developed (U.S. EPA, 1991). Despite these shortcomings, it was noted by EPA that the McNamara et al. data are the best available for estimating the carcinogenic potency of sulfur mustard. The authors of the EPA report analyzed two sets of McNamara s data one from a toxicity study and one from a carcinogenicity study (see Section 3.7.2). 

Benton et al. (2006b, 2007) experimentally determined the LCtso and LC50 in male and female adult SD rats exposed whole body to VX vapor for 10, 60, and 240 min in a dynamic exposure chamber (Table 6.3) study protocol was similar to that for agent GB in the studies conducted by Mioduszewski et al. (2001, 2002a). Experiments testing the role of decontamination less than 24 h post-exposure provided clear evidence for percutaneous toxicity induced by whole-body vapor exposure to the persistent nerve agent VX. For severe and lethal VX vapor exposure effects, females were not more susceptible than males for the exposure durations examined. 

No Observed Effect Level (NOEL) from Toxicity Data. The types of toxicity studies that are submitted In support of registration are similar throughout the world. In Canada there are no specific protocols delineated for the conduct of toxicity tests but most comply with those set under FIFRA, WHO. or OECD guidelines. The data requirements Include the tests outlined on Tables V, VI, and VII. These are guidelines, not rigid requirements, and the manufacturers are encouraged to discuss their data packages before completion. 

ICH 4.1.3 Assessment of Developmental Toxicity. This is almost identical to the segment II study protocol. Pregnant animals are exposed from implantation through organogenesis. The parameters measured in the segment II study are similar. However, the study is usually conducted using at least two species. More specifically, at least one rodent and one nonrodent species. 

Protocol Copy of the protocol for each conducted clinical study. Note that Phase 1 protocols should provide a brief outline, including estimation of number of subjects to be included, description of safety exclusions, and description of dosing plan (duration, dose, method). All protocols should address monitoring of blood chemistry and vital signs, and toxicity-based modification plans. 

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