Reproductive toxicity mechanism

Ronis MJJ, Gandy J, Badger T. 1998b. Endocrine mechanisms underlying reproductive toxicity in the developing rat chronically exposed to dietary lead. J Toxicol Environ Health 54 77-99. 

Data adequacy The key study was well designed, conducted, and documented used 20 human subjects and utilized a range of concentrations and exposure durations. Occupational exposures support the 8-h AEGL value. The mechanism of headache induction (vasodilation) is well understood and occurs following therapeutic administration of nitrate esters to humans. Animal studies utilized several mammalian species and addressed metabolism, neurotoxicity, developmental and reproductive toxicity, and potential carcinogenicity. ... 

Substantially less is known about the mechanism by which mirex causes reproductive toxicity. Mirex does not, however, appear to produce its reproductive toxicity by mimicking estrogen (Gellert 1978 Hammond et al. 1979). 

Less complex test systems, including nonmammalian and in vitro cultures, are recommended only for pre-screening or secondary studies to elucidate mechanisms. A useful statement for use with lACUC committees comes from this section, as follows In short, there are no alternative test systems to whole animals currently available for reproduction toxicity testing with the aims set out in the introduction. ... 

Improve and validate in vitro methods for assessing mechanisms of potential reproductive toxicity. 

Numerous diagnostic methods have been developed to evaluate female reproductive dysfunction. Although these methods have rarely been used for occupational or environmental toxicological evaluations, they may be helpful in defining biological parameters and mechanisms related to female reproductive toxicity. If clinical observations link exposure to the reproductive effect of concern, these data will aid the assessment of adverse female reproductive toxicity. The following clinical observations include end-points that may be reported in case reports or epidemiological research studies. 

A weight of evidence approach to assessing reproductive toxicity requires rigorous evaluation of all available data. However, often only limited information is available, and default assumptions must be made because of uncertainties in understanding mechanisms, dose-response relationships at low dose levels and human exposure patterns. Several of these assumptions are basic to the extrapolation of toxicity data from animals to humans, while others are specific to reproductive toxicity. The general default assumptions for reproductive toxicity stated in the IPCS (1995) report are summarized as follows ... 

Mattison DR Thomford PJ (1989) The mechanisms of action of reproductive toxicants. Toxicol Pathol, 17 364-376. 

The wealth of information in animals administered DEHP for periods ranging from a few days to lifetime studies indicate that DEHP is a developmental and reproductive toxicant by mechanisms not yet completely understood. As discussed below, the mechanisms do not appear to involve binding of DEHP to the estrogen or androgen receptors. DEHP administered perinatally to females is embryotoxic and teratogenic (reduced fetal body weight, increased rates of abortion and fetal resorptions, skeletal... 

In planning the studies, they must reflect human exposure to the medicinal product and allow specific identification of stages at risk. Furthermore, the anticipated drug use especially in relation to reproduction, the physical nature of the test substance and route of administration or exposure should be taken into account. Also any existing data on toxicity, pharmaco-dynamics, kinetics, mechanisms of reproductive toxicity in humans or known from previously conducted studies, and similarity to other class-related compounds in structure and activity should be taken into consideration. 

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