Defective spermatogenesis: Martin et al. respond

This is an Open Access article - Copyright @ National Institute of Environmental Health Science.BACKGROUND: Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. OBJECTIVES: We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α–mediated mode of action was specifically explored. RESULTS: We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. CONCLUSIONS: The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population

Catecholamines and Hepatic Drug Metabolism

The thesis embodies work designed to investigate the acute effects of catecholamines on the hepatic metabolism of foreign compounds. Most of the studies were performed on the isolated perfused liver of the rat. The historical development of the techniques used in the perfusion of the liver is reviewed. The literature concerning the properties of the hepatic mixed function system responsible for the metabolism of foreign compounds has been reviewed. Previous work on the effects of catecholamines on drug metabolism is also discussed. The operative procedure and the technique for the perfusion of the liver were developed to enable rapid transfer of the liver to the perfusion chamber without a period of anoxia, which has characterised many previous attempts at perfusion of the liver. The liver was perfused with a semisynthetic medium. The viability of the liver was assessed by a variety of tests of biochemical and physiological function and by histological examination. The technique developed allowed the liver to be successfully perfused for periods of up to 6 h, whilst maintaining a functional integrity. The metabolism of the type I and the type II substrates, hexobarbitone and aniline respectively, were investigated. Hexobarbitone is removed by a first order reaction at a rate comparable to that previously reported for the liver in vivo. Aniline metabolism, which has not previously been investigated in the perfused liver, was studied in some detail. Aniline is removed biphasically from the perfusion medium. Half of the aniline removed is converted to an acid-labile conjugate, possibly aniline-N-glucuronide, and a further 25% is converted to p-aminophenol and its conjugates. 3H-aniline added to the perfused liver could be quantitatively accounted for after 3 h perfusion. In agreement with previous findings, it was found that p-aminophenol reacts with haemoglobin, thus making it impossible to detect free p-aminophenol in the perfusion medium. The differences between the pattern of aniline metabolism by the perfused liver and by the whole animal, where aniline is excreted mainly as p-aminophenol and its conjugates, are discussed. The kinetics of aniline removal have been analysed by curve stripping and model fitting. The mathematics of these procedures are described separately in Appendix II. In the perfused liver aniline is distributed throughout a two-compartment system. The first compartment probably represents the total aqueous phase and aniline is removed from this compartment only. The identity of the second compartment is less certain. Several possibilities are discussed and in view of evidence obtained with SKF 525-A, an inhibitor of drug metabolism, it is suggested that the second compartment may represent the binding of aniline to a non-metabolic site of cytochrome P-450. Both adrenaline and noradrenaline inhibit the metabolism of hexobarbitone by the perfused liver but neither catecholamine has any effect on the metabolism of aniline. Catecholamines do not inhibit the metabolism of either aniline or hexobarbitone by the microsomal fraction or by liver slices. It was thus concluded that catecholamines are not inhibiting hexobarbitone removal directly. The possibility that their effect is mediated by cyclic AMP, a compound reported to inhibit hexobarbitone metabolism by the perfused liver, was investigated. Papaverine, an inhibitor Of phosphodiesterase, does not potentiate the inhibitory effects of catecholamines on hexobarbitone metabolism, nor does it cause them to have any inhibitory effect on the metabolism of aniline. Cyclic AMP was shown to inhibit drug metabolism by liver slices, whereas catecholamines are without effect. The probability that cyclic AMP is not important in mediating the effects of catecholamines on drug metabolism is discussed in some detail. Both catecholamines increase the portal pressure in the -perfused liver by over 100%. When Ca2+ is omitted from the perfusion medium it was found that this pressor effect is almost totally inhibited. Catecholamines also no longer in- hibit the metabolism of hexobarbitone. The omission of Ca2+ leaves the metabolic effects of catecholamines relatively unaffected. It was thus suggested that catecholamines might be inhibiting hexobarbitone metabolism through an effect on the hepatic vasculature. In a constant flow system, as used in this study, one way in which such an effect of catecholamines might manifest itself is as a redistribution of perfusate through the liver. It was found that considerable controversy exists as to whether or not catecholamines can cause a redistribution of blood flow within the liver. The available evidence is assessed separately in Appendix II. The effects of adrenaline on the intrahepatic distribution of perfusate have been investigated by X-radiography, and by perfusing the liver with Indian ink followed by histology. It was concluded from these studies that catecholamines can cause a redistribution of blood flow within the liver, away from the periphery of the lobes towards more central regions. (Abstract shortened by ProQuest.)

Increased Expression of Histone Proteins during Estrogen-Mediated Cell Proliferation

There is concern about the potential risk posed by compounds with estrogen-like activity present in the environment. As previous studies have shown that combined exposure to such compounds results in dose additivity, it should be possible to assess estrogen exposure with suitable biomarkers of effect

Improving selection of markers in nutrition research: evaluation of the criteria proposed by the ILSI Europe Marker Validation Initiative

The conduct of high-quality nutrition research requires the selection of appropriate markers as outcomes, for example as indicators of food or nutrient intake, nutritional status, health status or disease risk. Such selection requires detailed knowledge of the markers, and consideration of the factors that may influence their measurement, other than the effects of nutritional change. A framework to guide selection of markers within nutrition research studies would be a valuable tool for researchers. A multidisciplinary Expert Group set out to test criteria designed to aid the evaluation of candidate markers for their usefulness in nutrition research and subsequently to develop a scoring system for markers. The proposed criteria were tested using thirteen markers selected from a broad range of nutrition research fields. The result of this testing was a modified list of criteria and a template for evaluating a potential marker against the criteria. Subsequently, a semi-quantitative system for scoring a marker and an associated template were developed. This system will enable the evaluation and comparison of different candidate markers within the same field of nutrition research in order to identify their relative usefulness. The ranking criteria of proven, strong, medium or low are likely to vary according to research setting, research field and the type of tool used to assess the marker and therefore the considerations for scoring need to be determined in a setting-, field- and tool-specific manner. A database of such markers, their interpretation and range of possible values would be valuable to nutrition researchers

Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis // A síndrome da disgenesia testicular e a hipótese do estrogênio: uma meta-análise quantitativa

Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The only quantitative summary estimate of the link between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago; other reviews of the link between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α-mediated mode of action was specifically explored. Eight studies were included, investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. Results of the subset analyzes point to the existence of unidentified sources of heterogeneity between studies or within the study population

Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis

Background: Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive.// Objectives: We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α–mediated mode of action was specifically explored.// Results: We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer.// Conclusions: The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population

Scientific principles for the identification of endocrine-disrupting chemicals: a consensus statement

Endocrine disruption is a specific form of toxicity, where natural and/or anthropogenic chemicals, known as "endocrine disruptors" (EDs), trigger adverse health effects by disrupting the endogenous hormone system. There is need to harmonize guidance on the regulation of EDs, but this has been hampered by what appeared as a lack of consensus among scientists. This publication provides summary information about a consensus reached by a group of world-leading scientists that can serve as the basis for the development of ED criteria in relevant EU legislation. Twenty-three international scientists from different disciplines discussed principles and open questions on ED identification as outlined in a draft consensus paper at an expert meeting hosted by the German Federal Institute for Risk Assessment (BfR) in Berlin, Germany on 11-12 April 2016. Participants reached a consensus regarding scientific principles for the identification of EDs. The paper discusses the consensus reached on background, definition of an ED and related concepts, sources of uncertainty, scientific principles important for ED identification, and research needs. It highlights the difficulty in retrospectively reconstructing ED exposure, insufficient range of validated test systems for EDs, and some issues impacting on the evaluation of the risk from EDs, such as non-monotonic dose-response and thresholds, modes of action, and exposure assessment. This report provides the consensus statement on EDs agreed among all participating scientists. The meeting facilitated a productive debate and reduced a number of differences in views. It is expected that the consensus reached will serve as an important basis for the development of regulatory ED criteria

Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their revaluation

The threshold of toxicological concern (TTC) approach is a resource-effective de minimismethod for the safety assessment of chemicals, based on distributional analysis of the results of a large number of toxicological studies. It is being increasingly used to screen and prioritise substances with low exposure for which there is little or no toxicological information. The first step in the approach is the identification of substances that may be DNA-reactive mutagens, to which the lowest TTC value is applied. This TTC value was based on analysis of the cancer potency database and involved a number of assumptions that no longer reflect the state-of-the-science and some of which were not as transparent as they could have been. Hence, review and updating of the database is proposed, using inclusion and exclusion criteria reflecting current knowledge. A strategy for the selection of appropriate substances for TTC determination, based on consideration of weight of evidence for genotoxicity and carcinogenicity is outlined. Identification of substances that are carcinogenic by a DNA-reactive mutagenicmode of action and those that clearly act by a non-genotoxic mode of action will enable the protectiveness to be determined of both the TTC for DNA-reactive mutagenicityand that applied by default to substances that may be carcinogenic but are unlikely to be DNA-reactive mutagens (i.e. for Cramer class I-III compounds). Critical to the application of the TTC approach to substances that are likely to be DNA-reactive mutagens is the reliability of the software tools used to identify such compounds. Current methods for this task are reviewed and recommendations made for their application

Characterising vaping products in the UK: An analysis of Tobacco Products Directive notification data

Aims: To analyse content and emission data submitted by manufacturers for nicotine‐containing vaping products in the UK in accordance with the European Union Tobacco Products Directive.Design: Analysis of ingredient and emission data reported for all e‐liquid‐containing e‐cigarettes, cartridges or refill containers notified to the Medicines and Healthcare Regulatory Agency (MHRA) from November 2016 to October 2017.Setting: United KingdomCases: A total of 40,785 e‐liquid containing products.Measurements: The average number of ingredients per product, nicotine concentrations, frequency of occurrence ingredients and frequency and levels of chemical emissions.Findings: Reports were not standardised in relation to units of measurement or constituent nomenclature. Products listed an average of 17 ingredients and 3.3% were reported not to contain nicotine. 59% of products contained less than 12 mg nicotine per mL, and less than 1% were reported to have nicotine concentrations above the legal limit of 20 mg/mL. Over 1500 ingredients were reported, and other than nicotine the most commonly reported non-flavour ingredients were propylene glycol (97% of products) and glycerol (71%). The most common flavour ingredients were ethyl butyrate (42%), vanillin (35%) and ethyl maltol (33%). The most frequently reported chemical emissions were nicotine (65%), formaldehyde (48%) and acetaldehyde (40%). The reporting of the concentration of emissions was not standardised; emissions were reported in a format allowing analysis of median estimated concentration for between 13% and 100% of products for each reported emission. Most of the frequently reported emissions, other than nicotine, were present in median estimated concentrations below 1 μg/L of inspired air, and with the exception of nicotine, acrolein and diacetyl, at median levels below European Chemicals Agency Long Term Exposure and United States (US) Department of Labor Occupational Safety and Health Administration (OSHA) limits, where these were available