Reproductive toxicity and teratogenicity

Mutagenicity tests are usually carried out in vitro and in vivo, often using both prokaryotic and eukaryotic organisms. A well-known example is the Ames test, which assesses the ability of a drug to induce mutation reversions in E. coli and Salmonella typhimurium. 

Longer-term carcinogenicity tests are undertaken, particularly if (a) the product s likely therapeutic indication will necessitate its administration over prolonged periods (a few weeks or more) or (b) if there is any reason to suspect that the active ingredient or other constituents could be carcinogenic. These tests normally entail ongoing administration of the product to rodents at various dosage levels for periods of up to (or above) 2 years. 

Many drugs are administered to localized areas within the body by, for example, subcutaneous (s.c.) or intramuscular (i.m.) injection. Local toxicity tests appraise whether there is any associated toxicity at/surrounding the site of injection. Predictably, these are generally carried out by s.c. or i.m. injection of product to test animals, followed by observation of the site of injection. The exact cause of any adverse response noted (i.e. active ingredient or excipient) is usually determined by their separate subsequent administration. 

The indicator molecule serves to assess the state of health of the cultured cells. The dye, neutral red, is often used (healthy cells assimilate the dye, dead cells do not). The major drawback to such systems is that they do not reflect the complexities of living animals and, hence, may not accurately reflect likely results of whole-body toxicity studies. Regulatory authorities are (rightly) slow to allow replacement of animal-based test protocols until the replacement system has been shown to be reliable and is fully validated. 

In addition, tests for mutagenicity and carcinogenicity are probably not required for most biopharmaceutical substances. The regulatory guidelines and industrial practices relating to biopharmaceutical pre-clinical trials thus remain in an evolutionary mode. 

Because both males and females are treated in this type of study design, it is not possible to distinguish between maternal and paternal effects in the reproductive performance. To permit this separation, it is necessary to dose additional animals to the stage of mating and then breed them to untreated members of the opposite sex. Similarly, if effects are seen postnatally, it may not be possible to distinguish between effects mediated in utero or mediated by lactation. This distinction can be made by cross-fostering the offspring of treated females to untreated females, and vice versa. 

The end points observed in these types of tests, depending on study design, are as follows  

Fertility index, the number of pregnancies relative to the number of matings. 

The number of live births, relative to the number of total births. 

Pre-implantation loss, or number of corpora lutea in the ovaries relative to the number of implantation sites. 

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Thiabendazole Based on a range of end-points - effects on liver, spleen, thyroid, reproductive toxicity and teratogenicity (10 mg/kg bw/day) 100 0.1... 

In the case of compounds that have been found to have treatment-related effects on reproduction or EFD in animals, the magnitude of the doses selected for the study can have important implications for risk assessment. The position of the doses on the dose-response curve can influence the nature of the findings. A theoretical dose-response curve for developmental toxicity and teratogenicity is depicted in Fig. 1. Depending on the doses applied and the nature of the dose-response, the results obtained will vary. 

A selective compilation of papers on safety evaluation and regulation of chemicals, including the impact of regulations and improvement of methods, has been published as a book, edited by Homburger (ref. 13). Out of 34 papers, two are devoted directly to teratogens and address current in vivo reproductive toxicity and teratology methods, and new perspectives in tests for teratogenicity. 

Chronic toxicity, reproductive effects, and teratogenic, mutagenic, and carcinogenic effects of Folpet are described in the above reference (Federal Register). The half-life of Folpet in human blood is about 1 min Folpet degrades rapidly to phthalimide and ultimately to phthalic acid and ammonia. 

Regarding reproductive toxicity, the teratogenic effects in fetuses were observed in [38] and the study in rats by [29] however, it is reasonable to consider that the observed effects are not the direct effects of test substance but the secondary effects derived from the maternal toxicity. In general, a threshold exists for teratogenicity and when some maternal toxicity occurs, fetal anomaly is observed. Therefore, a dose without any maternal toxicity can be used for risk assessment as the no observed effect level (NOEL) for teratogenicity. Consequently, the NOAEL for developmental effect is established as 500 mg kg per day. 

Teratogenicity, embryotoxicity, irreversible reproductive toxicity, and myelotoxicity have been observed in animals at ganciclovir dosages comparable with those used in human beings. Ganciclovir is classified in pregnancy as category C. 

Reproductive Toxicity. No data are available that impHcate either hexavalent or trivalent chromium compounds as reproductive toxins, unless exposure is by way of injection. The observed teratogenic effects of sodium dichromate(VI), chromic acid, and chromium (HI) chloride, adininistered by injection, as measured by dose-response relationships are close to the amount that would be lethal to the embryo, a common trait of many compounds (111). Reported teratogenic studies on hamsters (117,118), the mouse (119—121), and rabbits (122) have shown increased incidence of cleft palate, no effect, and testicular degeneration, respectively. Although the exposures for these experiments were provided by injections, in the final study (122) oral, inhalation, and dermal routes were also tried, and no testicular degeneration was found by these paths. 

There has been no comprehensive evaluation of the reproductive and developmental effects of hexachloroethane. Limited data indicate that it is maternally toxic and retards fetal development. It does not appear to be a teratogen. 

Christian, M.S. (1983). Assessment of reproductive toxicity State of the art. In Assessment of Reproductive and Teratogenic Hazards (Christian, M.S., Galbraith, M., Voytek, P. and Mehlman, M.A., Eds.). Princeton Scientific Publishers, Princeton, pp. 65-76. 

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. 

Reproductive toxicity of acesulfame K was studied in test systems aimed at detecting teratogenicity, oral embiyotoxicity and in a multigeneration study. No teratogenicity, no embryotoxicity, and no effects on reproduction, development of the fetuses and lactation performance were found.7... 

The three targets that are the first point of contact between environmental chemicals and the body will be discussed first the gastrointestinal tract, the respiratory system, and the skin. Recall from Chapter 2 that chemicals enter the blood after absorption, so this fluid is the next target (see Figure 2.1). Then come the liver, the kidneys, and the nervous system. The chapter concludes with a discussion of some chemicals that can damage the reproductive system and some that can cause birth defects, the so-called teratogens, and other forms of developmental toxicity. Brief discussions of immune system, cardiovascular system, muscle, and endocrine system toxicities are also offered. 

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