Reproductive toxicity dose-response relationships

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. 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

One dose level is tested, usually the higjiest dose associated with the production of minimal toxic effects, but without affecting reproductive behavior or survival. To establish a dose—response relationship, two additional lower doses are required. 

Existing data indicate that nickel is a reproductive toxicant in animals, although a clear dose-response relationship has not been identified. Occupational exposure to high concentrations of nickel may result in reproductive effects in humans, but it is unlikely that exposure to nickel at low levels expected at hazardous waste sites would result in reproductive effects. 

Hemminki, K., Paasivirta, J., Kurkirinne, T. Virkki, L. (1980) Alkylation products of DNA bases by simple epoxides. Chem.-biol. Interact., 30, 259-270 Hine, C.H., Kodama, J.K., Wellington, J.S., Dunlap, M.K. Anderson H.H. (1956) The toxicology of glycidol and some glycidyl ethers. Arch. ind. Health, 14, 250-264 Hooper, K., LaDou, J., Rosenbaum, J.S. Book, S.A. (1992) Regulation of priority carcinogens and reproductive or developmental toxicants. Am. J. ind. Med., 22, 793-808 Hussain, S. (1984) Dose-response relationships for mutations induced in E. coli by some model compounds. Hereditas, 101, 57-68... 

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 ... 

The evaluation of dose-response relationships is a critical component of hazard characterization (OECD, 1989 ECETOC, 1992 US , 1997a IPCS, 1999). Evidence for a dose-response relationship is an important criterion in establishing a toxic reproductive effect. It includes the evaluation of data from both human and laboratory animal studies. Because quantitative data on human dose-response relationships are infrequently available, the dose-response evaluation is usually based on the assessment of data from tests performed using laboratory animals. However, if data are available in humans with a sufficient range of doses, dose-response relationships in humans can also be evaluated. 

No oral MRL has been derived for chromium(VI) or chromium(III) because a NOAEL for reproductive effects has not been adequately characterized. Additional studies are needed to identify a threshold for toxicity and establish dose-response relationships. However, any MRL derived for the oral route would have to take into consideration the essentiality of chromium. No dermal studies of intermediate duration in animals were located. The toxicity of intermediate-duration exposure to chromium compounds is relatively well characterized for the oral and inhalation routes. Dermal studies would be useful to determine possible target organs other than the skin. There are populations surrounding hazardous waste sites that might be exposed to the substance for similar durations. 

Once an assessment has determined that the data indicate human risk potential, the next step is to perform a quantitative evaluation. Here, dose-response data from human and animal reproductive and developmental toxicity studies are analyzed to select LOAELs and NOAELs or to calculate a BMD. The assessment should use quantitative human dose-response data if the data span a sufficient range of exposure. Because data on human dose-response relationships are rarely available, the dose-response evaluation is usually based on an assessment of data from tests performed in experimental animals. 

The RACB studies were designed by NTP to test chemicals for potential reproductive toxicity in males and females. In addition, this two-generation study design can be used to characterize the toxicity and to define the dose-response relationship for each chemical. 

First, reproductive and developmental lead toxicity in both men and women remains a significant human health issue on several grounds, whether adequately characterized in terms of dose—response relationships or not. Occupational lead exposures remain as sources of toxicity in both industrialized and developing countries. These exposures of both male and female workers potentially persist at levels not greatly different from those reported in past decades. 

The database for HFC-134a is extensive it contains studies with both human subjects and animal models. Potentially sensitive populations, including patients with COPD and adult and pediatric asthmatic patients, were tested with direct inhalation of HFC-134a from metered-dose inhalers. The response of these groups was no different than that of healthy adults. The animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The metabolism of HFC-134a is well understood, and the relationship of exposure con... 

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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