Non-monotonic dose responses

Kopp-Schneider, A., and Lutz, W. K. (2001). J-shaped dose-response relationship for tumor induction by caffeic acid in the rat forestomach, modeled by non-monotonic dose response for DNA damage and cell proliferation. HERA 7, 921-931. 

One of the best known controversies of endocrine disraptors concerns bisphenol-A (BPA). For researchers who conducted toxicological research on BPA, the scientific debate touches upon several aspects of risk. Generally for endocrine dismpters, the points in contradiction concern the existence of non-monotonic dose-response relationships, the relevance of proof of the physiological nature which seems to confirm the effects of low doses, and the importance of critical windows of exposure. Vandenberg et al. [VAN 09] analyzed in detail the scientific literature on BPA, including whether ... 

FIGURE 7.2 Examples of non-monotonic dose-response cnrves. Above Effect of tnmor volume in mice on the BPA levels in drinking water shows an inverted-U response. Numbers on the horizontal axis refer to pg BPA/1 of drinking water available to the mice. These correspond to 0-500 pg of BPA/kg body weight. Below Suppression of adiponectin release from human breast adipose explants by BPA and estradiol (E ). (Hugo et al., 2008). Source Jenkins et al. (2011). 

Andrade AJ, Grande SW, Talsness CE, Grote K, Chahoud I. A dose-response study following in utero and lactational exposure to di(2-ethylhexyl)-phthalate (DEHP) non-monotonic dose-response and low dose effects on rat brain aromatase activity. Toxicology. Oct 29, 2006 227(3) 185-192. 

Jenkins S, Wang J, Eltoum I, Desmond R, Lamartiniere CA, (2011). Chronic oral exposure to bisphenol A results in a non-monotonic dose response in mammary carcinogenesis and metastasis in MMTV-erbB2 mice. Environ Health Perspect, 119, 164-1609. 

Insights from research offer new opportunities for prevention of chronic diseases, based on scientific understanding of low-dose effects, non-monotonic dose responses, mixture toxicity, developmental origins of health and disease, and epigenetics. 

Dilleen, M., Heimann, G., and Hirsch, I. Non-parametric estimators of a monotonic dose-response curve and bootstrap confidence intervals. Statistics in Medicine 2003 22 869-882. 

Usually, the dose-effect relationship P(D) is simplified to the single quantitative or even qualitative characteristic. For example, for a certain level of probability q it is possible to determine an appropriate characteristic dose (quantile) Dg = Arg P(D) = q. Most often, the ED50 for q = 0.5 values are used, but = 0.16, q = Q.15, = 0.84 are also considered sometimes. However, for a non-monotonic dependence of P D), Dg can be ambiguous or even not exist if P D)< q for instance if (i) the part of population is resistant to the acting compounds and (ii) the suggested threshold q exceeds the fraction of the responsible part of population. 

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