Gochfeld Michael
Environmental and Occupational Health Sciences Institute, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.
Environ Res. 2007 May;104(1):4-21. doi: 10.1016/j.envres.2005.12.005. Epub 2006 Apr 17.
Differences in exposure, anatomy, physiology, biochemistry, and behavior between males and females are a dominant theme in biology, transcending the plant and animal kingdoms. Yet differences due to sex and gender have not received adequate attention in human or animal toxicology nor always in epidemiology. Generalizations are often made about species' responses to xenobiotics, without data or consideration of female/male differences. Despite the leading role that pharmacology and drug development play in elucidating toxicokinetics, gender studies are relatively recent. Phenomenologic or clinical observations of sex differences often go unexplored, but pharmaceutical companies recognize the importance of enhanced understanding of toxicokinetics and toxicodynamics and emphasize the value of translational or integrational research--bringing laboratory findings to bedside applications and bedside questions to laboratory study. However, for many years Food and Drug Administration guidelines specifically precluded participation of females in many drug studies. Many occupational epidemiology studies, on which much of our understanding of toxic effects is based, begin by excluding women and minorities. Sex differentiation begins in the embryo under genetic and hormonal control. Changes affecting exposure, susceptibility, risk, and health continue throughout life. This paper provides a framework for analyzing the level(s) at which gender differences arise. The framework addresses exposure, toxicokinetics, toxicodynamics, and modulating influences. Men and women differ in many aspects of vulnerability to xenobiotics and other stressors, beginning with their opportunities for exposure. Toxicokinetic differences mainly involve metabolism, with few differences in absorption yet demonstrated. In addition, lifestyle, psychosocial, and hormonal factors modify the kinetics and responsiveness. Some phenomena fit the Classic Sex Hormone Paradigm in which castration (with and without hormone replacement) and administration of the opposite sex hormone demonstrate the primary regulatory role of sex hormones. Many phenomena, however, differ between males and females without showing a clear-cut relationship with the sex hormones. Since every cell both has a sex chromosome (X or Y) and is exposed to hormones, elegant techniques are just beginning to tease apart genetic from hormonal influences. Wherever possible, studies should use balanced gender and gender x age designs and should analyze data by sex and interactions, rather than simply adjusting for (discarding) gender. Power should be adequate, or lack of power (if inevitable) should be clearly stated.
雄性和雌性在暴露、解剖学、生理学、生物化学及行为方面的差异是生物学中的一个主要议题，跨越了植物和动物界。然而，性别和社会性别差异在人类或动物毒理学中并未得到充分关注，在流行病学中也并非总是如此。人们常常在没有数据或未考虑雌雄差异的情况下，对物种对外源化学物的反应进行概括。尽管药理学和药物研发在阐明毒代动力学方面发挥着主导作用，但性别研究相对较新。性别差异的现象学或临床观察往往未得到深入探讨，但制药公司认识到深入理解毒代动力学和毒效动力学的重要性，并强调转化或整合研究的价值——将实验室研究结果应用于临床实践，并将临床问题带回实验室研究。然而，多年来，美国食品药品监督管理局的指导方针明确禁止女性参与许多药物研究。许多职业流行病学研究（我们对毒性作用的许多认识都基于这些研究）一开始就排除了女性和少数族裔。性别分化在胚胎期就已在基因和激素的控制下开始。影响暴露、易感性、风险和健康的变化贯穿一生。本文提供了一个分析性别差异产生层面的框架。该框架涉及暴露、毒代动力学、毒效动力学及调节影响。男性和女性在对外源化学物及其他应激源的易感性的许多方面存在差异，首先体现在他们的暴露机会上。毒代动力学差异主要涉及代谢，目前尚未发现吸收方面有明显差异。此外，生活方式、心理社会因素和激素因素会改变动力学和反应性。一些现象符合经典性激素范式，即去势（有无激素替代）和给予异性激素可证明性激素的主要调节作用。然而，许多现象在雄性和雌性之间存在差异，但与性激素并无明确关系。由于每个细胞都既有性染色体（X或Y）又暴露于激素之下，精妙的技术才刚刚开始区分基因影响和激素影响。只要有可能，研究应采用平衡的性别和性别×年龄设计，并应按性别及相互作用分析数据，而不是简单地对性别进行调整（舍弃）。样本量应足够，或者（如果不可避免）应明确说明样本量不足的情况。
