Threshold analysis of selected dose‐response data for endocrine active chemicalsNote
Using a biologically relevant mathematical model, the Michaelis-Menten equation, we examined published data from endocrine active chemicals for evidence of no-threshold dose-response curves. Data were fit to a modified Michaelis-Menten equation which accounted for total background response. Subsequently, the data sets were analyzed using non-linear regression in order to estimate the four parameters of interest (non-hormone controlled background (Bnh), maximum response (Rmax), endogenous hormone level (D0), and the dose at which a half-maximal response was observed (ED50)) and to determine the fit to the fully modified Michaelis-Menten equation. Subsequently, response data were adjusted to account for Bnh and then normalized to Rmax, while dose data were adjusted to account for D0 and then normalized to the ED50. This data set was combined into a single, composite data set and fit to the fully modified Michaelis-Menten equation. We examined 31 data sets (24 endpoints) from studies on 9 different chemical/hormone treatments. Twenty-six of the data sets fit the modified Michaelis-Menten equation with high multiple correlation coefficients (r>0.90). The normalized data demonstrated a good fit to the modified Michaelis-Menten equation. These results indicate that a variety of biological responses fit the modified Michaelis-Menten equation, which does not have a threshold dose term.
- [Show abstract] [Hide abstract] ABSTRACT: For human populations a hypothesis has been put forward that increased incidence of breast and testicular cancers, and aspects of reduced reproductive function, especially in males, is caused by an increased exposure to endocrine disrupters (EDs). This paper overviews the evidence for these links and expands them to the data relative to neurotoxicity, thyroid-and immunomodulation caused by EDs. Wildlife data are considered to the extent that they may be relevant to the health issues for humans. The available data are discussed in a context of the risk assessment paradigm: hazard identification, dose-response assessment, exposure assessment, and risk characterisation. The underlying aim is to investigate the possibility of quantifying the risks caused by EDs. Although no definitive proof exists, there is increasingly sound evidence for the ED hypothesis. It is, however, not possible to quantify the health consequences of ED exposure in a reliable way. Fundamental information is currently lacking for each of the steps of the risk assessment paradigm. The most important knowledge gaps concern: the availability of a validated set of EDs tests, knowledge on the mechanisms through which EDs act, an integrated exposure assessment of EDs as a group, exposure and effects at sensitive periods of development, and validated dose-response relationships for effects caused by EDs. An attempt to quantify the effects of EDs is an interesting exercise in rendering gaps in knowledge and making understanding clear and transparent. These gaps provide the basis for the controversy which exists on the need for regulation of EDs. While waiting for more results of studies unravelling the relationship between EDs in the environment and adverse health effects, a policy attitude based upon the ‘precautionary principle’ seems to be the only sensible one.0Comments 4Citations
- [Show abstract] [Hide abstract] ABSTRACT: Environmental contaminants with estrogenic properties have been cause for heightened concern about their possible role in inducing adverse health effects. Brief exposure of rodents to high doses of natural estrogens early in life results in permanent alterations of the male reproductive tissues, but the question of whether environmentally relevant doses can cause the same effects remains controversial. The current project was designed to determine the dose-response relationship between neonatal estradiol exposure and the development of the male reproductive tract in the rat. Neonatal male Sprague-Dawley (SD) and Fisher 344 (F344) rats were exposed to beta-estradiol-3-benzoate (EB) at concentrations ranging from 0.015 microg/kg body weight (BW) to 15.0 mg/kg BW and 0.15 microg/kg BW to 1.5 mg/kg BW, respectively. Results showed an inverted U-shaped dose-response profile for testis and epididymis weights in 35-day-old SD rats, with increased organ sizes at the low-dose end of the treatment. This effect was transient and was not sustained into adulthood. Increased hepatic testosterone hydroxylase activities in low-dose animals suggest an advancement of puberty as the cause for increased reproductive organ weights. On postnatal day (PND) 90, a stimulatory low-dose response to EB was present in SD rat testicular and epididymal weights, however at one order of magnitude lower dose than that seen on PND 35, suggesting a separate effect. All SD male reproductive tract organs and serum hormones showed a permanent inhibitory response to high doses of neonatal EB. F344 rats exhibited greater estrogen sensitivity on PND 90. Despite this heightened responsiveness, F344 rats did not exhibit a low-dose effect for any endpoint. These low-dose responses to estradiol are organ and strain specific.0Comments 55Citations
- [Show abstract] [Hide abstract] ABSTRACT: Clenbuterol (CLEN), diethylstilbestrol (DES) and trenbolone (TbOH) are xenobiotic growth promoters and have been illegally applied as repartitioning agents in meat-producing animals. In the EU, proper detection methods and control systems are established for many hormones and anabolic substances, and therefore there is a need to improve the accuracy and repeatability of quantification. In order to define a common basis for accurate measurement and quantification, standard materials were produced as lyophilised bovine urine: ‘negative’ drug free controls, and ‘positive’ standards (CLEN ∼3 μg kg−1; DES ∼2 μg kg−1, TbOH ∼3 μg kg−1). Two milligram of CLEN or DES were applied orally in milk replacer to the calves. Two gram of TbOH-acetate was given as an implant. ‘Positive’ urine was sampled frequently between 12 and 24 h after application. ‘Negative’ urine was sampled from untreated calves only fed with milk replacer. Urines were pooled separately and diluted with ‘negative’ urine to a suitable level of final concentrations. Exactly 5.0 g portions of each standard were weighed into 750 brown glass containers and lyophilised in one batch. Container filling, dry matter and residual water content were determined and optimized. A 3-year stability and homogeneity study at various storage temperatures (−20 °C, +4 °C and +20 °C and +37 °C) indicate that all standards are stable and homogeneous. Reconstituted urines were quantified via ELISA and findings after reconstitution remained constant in ‘positive’ (+) standards and ‘negative’ (−) controls: CLEN+ (2.75±0.62 μg kg−1; n=133), CLEN− (0.023 μg kg−1 equivalents; n=130), DES+ (1.75±0.52 μg kg−1; n=133), DES− (0.034 μg kg−1 equivalents; n=133), TbOH+ (2.78±0.47 μg kg−1; n=133), TbOH− (0.022 μg kg−1 equivalents; n=133). Additionally, concentrations and identities of the drugs were confirmed by two independent accredited laboratories via HPLC–ELISA, LC–MS and GC–MS.0Comments 20Citations