Reproductive toxicology, examples

Reproductive Toxicology (mammalian) The study of the effects of chemicals on the adult reproductive and neuroendocrine systems, the embryo, foetus, neonate and prepubertal mammal. Reproductive Toxins Tire tenn refers to a specific target organ characterization of effect. These are chemicals which affect the reproductive capabilities including chromosomal damage (mutations) and effects on fetuses (teratogenesis). Signs and symptoms include birth defects sterility. Examples are lead and DBCP. 

Like the process chemistry modifications and formnlation development, the nonclinical evalnation process continnes well past the IND enabling phase. Additional preclinical evalnation will be necessary. For example, if human beings of reproductive age will be treated by the drug, reproductive toxicology will be necessary before an NDA can be filed, and if the drug is to be dosed chronically, carcinogenicity studies will be required. The nonclinical evaluation process continues throughout the clinical development. 

Most of the selected female reproductive toxicology studies examined explicitly stated chemical exposure levels either as parts per million, stratifying as to number of days of exposure, or as estimates of the percentage of the threshold limit values. Medline, Toxline, and Dissertation Abstracts databases were utilized to search for all research papers published in any language from 1966 to 1996. In total, 559 studies were obtained from the literature search. Of these, only 21 studies explicitly stated some sort of exposure level for the various chemicals. These chemical exposure levels in the literature and subsequent pregnancy outcomes were compared to lOL chemical exposure indices. The following is an example of one of the many chemical exposures encountered, namely exposure to toluene. For other compounds, Table 20.3.5 contrasts values in the literature with lOL indices of chemical exposure. 

Of utmost importance is the need in published occupational reports for some industrial hygiene documentation. Specifically, improved reporting of a quantifiable chemical exposure dose (for example, as implemented and currently utilized by lOL) and ideally a standard and consistent way of reporting this in the occupational literature pertaining to human reproductive toxicology. 

In most standard development programs, no investigations have been carried out to define the maternal toxicity whether, for example, stress hormones have been increased. If there is reason to believe that maternal toxicity is an important factor, then the submission documents should contain a comparison with the toxicity seen in the repeat-dose toxicology studies and the doses at which the toxicity occurred. If reproductive effects have been found at doses below those found to induce demonstrable toxicity in the repeat-dose studies, care should be taken in concluding that maternal toxicity has been a factor. In this context, the possibility of differences in sensitivity between pregnant and nonpregnant animals should also be considered. 

The chemical should not contain any chemicals that are a carcinogen or that are known to cause reproductive toxicity. Carcinogens are defined as those chemicals listed in the current edition of the Annual Report on Carcinogens, U.S. Department of Health and Human Services, National Toxicology Program. Chemicals known to cause reproductive toxicity, for example, are defined as those hsted by the state of California under the Safe Drinking Water and Toxic Enforcement Act of 1986 (Cah-fomia Code of Regulations, Title 22, Division 2, Subdivision 1, Chapter 3, Sections 1200, et seq.)... 

---