Dose-response relationship teratogens

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. 

An additional assessment factor, of up to 10, has been apphed in some cases where the NOAEL has been derived for a critical effect, which is considered as a severe and irreversible effect, such as teratogenicity or non-genotoxic carcinogenicity, especially if associated with a shallow dose-response relationship. The principal rationale for an additional factor for nature of toxicity has been to provide a greater margin between the exposure of any particularly susceptible humans and the dose-response curve for such toxicity in experimental animals. 

A foreign compound, which may act in this way is the herbicide nitrofen (2,4-dichloro-4 -nitro diphenyl ether), which causes a variety of malformations lethal to the neonate. There is no growth retardation or embryolethality at doses, which are teratogenic, however (Fig. 6.27), and therefore this exhibits the first type of dose-response relationship (see above). The... 

Figure 7.73 Dose-response relationship for diphenylhydantoin teratogene-sis. The incidence of cleft palate in the surviving embryos is plotted against the dose of diphenylhydantoin given to pregnant mice on days 11, 12, and 13 of gestation. Source From Ref. 21.

The association between benzene exposure and leukemia has been made since the late nineteenth century however, the dose-response relationship and mechanistic explanation have been quite contentious. The most reliable evidence associating chronic benzene exposure with AML was presented in a retrospective NIOSH study of rubber hydrochloride workers in Akron, OH, from 1940 to 1949. Unfortunately, the mechanism of how benzene exposure leads to the development of AML is not known. The two most frequently discussed potential mechanisms of toxicity involve either a point mutation or a chromosomal deletion. The latter is considered more likely since neither benzene nor its metabolites are mutagenic or teratogenic. 

Antilaminin antibodies induced by mercuric chloride have been demonstrated to be detrimental to the development of cultured rat embryos (Chambers and Klein 1993). Based upon that observation, those authors suggested that it might be possible for an autoimmune disease induced by a substance such as mercury at an early age to persist into later life, acting as a teratogen independent of both dose-response relationships and time of exposure, but that possibility remains to be experimentally demonstrated. 

FIGURE 6.16 Dose-response relationship patterns for different types of teratogen. Adapted from Manson, J.M., Teratogens, in Casarett and DoulF Toxicology, edited by C.D.Klaassen, M.O.Amdur and J.Doull (New York Macmillan), 3rd Edition, 1986. 

FIGURE 7.48 Embryolethality and teratogenicity of actinomycin D. This graph shows the dose-response relationship for these two toxic effects. Data from Wilson (1965) Ann. N.Y.Acad. Sci., 123,119. 

Teratogenic effects of substances on test animals are evaluated from resorption (death of the conceptus), fetal toxicity (reduced body weight), aberrations (malformations), and minor anomalies. Statistical analysis is performed by surveying the four most important parameters namely, the number of litters with malformed fetuses, increase in the average number of fetuses with defects per litter, the number of resorptions, and dead fetuses. Finally, the incidence of malformation (response) is plotted against doses administered. Any dose-response relationship should indicate the teratogenicity of the chemical under experimental conditions. 

Hazard characterization consists of qualitative or quantitative evaluation of the adverse health effects associated with different agents, whether they are chemicals or microorganisms. This step comprises several elements, like toxicokinetics (absorption, distribution, metabolism, and excretion of the toxic agent), mechanism of toxic action, dose-response relationships, target organs and different end points, like acute or chronic toxicity, teratogenicity, neoplastic manifestations, and so forth. 

Hazard evaluation is used here to mean examination and evaluation of the hazards (adverse effects) observed in toxicity studies, including reproductive, teratogenic, and general toxicity studies plus other pertinent data. Because of the complexities of the reproductive system as well as embryogenesis and maturation of the conceptus, hazard evaluations must go beyond the mere determination of statistical effects, no observed effect levels (NOELS), relationships between dose and response, dose and effects, and the determination of margins of safety. Most... 

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