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Reply to Increased cancer burden among pesticide applicators and others due to pesticide exposure
CA: A Cancer Journal for Clinicians ( IF 254.7 ) Pub Date : 2013-05-30 , DOI: 10.3322/caac.21193
Michael C R Alavanja 1 , Matthew K Ross , Matthew R Bonner
Affiliation  

Response to: Gray JW et al. By: Alavanja MCR, Ross MK, Bonner MR Gray et al. raise several important issues and we are grateful for the opportunity to continue the discussion regarding pesticides and their potential for carcinogenicity to humans. Gray et al. posit that a 7 to 18% deficit of cancer among pesticide applicators and their spouses in the Agricultural Health Study cohort (Koutros et al., 2010) is compelling evidence that pesticides are not associated with cancer. Of course Gray et al. are aware of the vast epidemiological literature that establishes that farmers in the United States are at a reduced risk of cancer overall, in large part because farmers smoke much less tobacco than the general population. Conversely, many epidemiologic studies, using a more rigorous methodology, cited in our table 5, show significant exposure-response patterns linking a particular pesticide to a particular cancer after carefully controlling smoking and other potential confounders. We think most scientists would agree that observing a statistically significant exposure-response relationship between a pesticide and a cancer has more etiologic meaning than the indirect and uncontrolled observation made by Gray et al. In our review we make no conclusion regarding the relationship between 2, 4-D and non-Hodgkin lymphoma because NHL is a complex disease and relatively few epidemiologic studies with cell-type specific data relevant to NHL etiology are available. We do highlight other widely-used pesticides that show etiologic evidence of human cancer (e.g., terbufos and malathion with aggressive prostate cancer, diazinon with lung cancer) and say the implications of this new evidence to public health needs serious consideration. In a field as dynamic as cancer etiology, we find it curious that Gray et al. rely on an International Agency of Research on Cancer (IARC) document from 1987 that makes a conclusion about the adequacy of the carcinogenicity data on any compound. There have been major leaps in understanding the biology and etiology of cancer in the past 26 years and we think a comprehensive scientific review of the extant literature on the association between specific pesticides and specific cancers by IARC is greatly needed. Gray et al. also argue that animal toxicity testing of pesticides performed by private chemical companies and the EPA have adequately demonstrated that these compounds do not pose a significant health risk to humans. Although animal models are absolutely necessary to predict toxicities in humans that might occur following exposure to environmental chemicals, they are not sufficient for public health surveillance and protection. This issue has been amply demonstrated in the pharmaceutical industry during the development of drugs. Indeed, human drug development is often stymied by unpredictable adverse health effects that arise in clinical trials, but were not predicted by either pre-clinical animal models or human cell culture experimentation (Sun et al., 2012). Furthermore, environmental toxicants such as arsenic, which have been shown to be highly toxic in humans in epidemiologic studies, do not concord with animal models of toxicity (Kitchin and Conolly, 2010). New strategies using quantitative high-throughput screening (qHTS) technology with human cells to identify toxicity pathways and molecular mechanisms leading to the prediction of an in vivo response will become valuable tools in the future (Sun et al., 2012). Gray et al. state that: “Hypothesizing alternative mechanisms of cancer causation for these well studied compounds relying on a minimal number of exploratory molecular studies appears blatantly speculative in comparison to the rich animal toxicology database”, and that “Reaching for new pathways to toxicity needs to seriously consider the substantial mass of current understanding and justify departure from well-established principles.” Unfortunately, it is not so clear that the mechanisms by which many environmental chemicals cause cancer actually do follow the “well-established principles”. Indeed, a chemical found to be negative in simple genotoxicity assays or lifetime animal bioassays could still contribute to human cancer formation by a variety of potential mechanisms, including epigenetic, endocrine disrupting, and pro-inflammatory pathways – none of which rely on genotoxicity. These mechanisms are important aspects of the current understanding of the carcinogenic process (Schottefeld and Fraumeni, 2006); they are certainly not ‘blatantly speculative’. Evaluating the health effects of pesticides in humans via epidemiologic studies, and molecular epidemiologic and toxicologic studies to evaluate mechanisms important to humans will be necessary to safeguard health.

中文翻译:

对农药施药者和其他人因接触农药而增加的癌症负担的答复

回应:Gray JW 等人。作者:Alavanja MCR、Ross MK、Bonner MR Gray 等。提出几个重要问题,我们感谢有机会继续讨论农药及其对人类致癌的可能性。格雷等人。假设在农业健康研究队列(Koutros 等人,2010 年)中,农药施用者及其配偶患癌症的比例为 7% 至 18%,这是农药与癌症无关的令人信服的证据。当然,格雷等人。意识到大量流行病学文献表明,美国农民总体患癌症的风险较低,这在很大程度上是因为农民吸烟的烟草比一般人群少得多。相反,我们表 5 中引用的许多流行病学研究使用了更严格的方法,在仔细控制吸烟和其他潜在混杂因素后,显示出将特定农药与特定癌症联系起来的显着暴露-反应模式。我们认为大多数科学家都会同意,与 Gray 等人进行的间接和不受控制的观察相比,观察农药和癌症之间具有统计学意义的暴露-反应关系具有更多的病因学意义。在我们的综述中,我们没有得出关于 2、4-D 和非霍奇金淋巴瘤之间关系的结论,因为 NHL 是一种复杂的疾病,并且可用的与 NHL 病因学相关的细胞类型特异性数据的流行病学研究相对较少。我们确实强调了其他广泛使用的杀虫剂,这些杀虫剂显示出人类癌症的病因学证据(例如,具有侵袭性前列腺癌的特布福斯和马拉硫磷,二嗪农与肺癌)并说这一新证据对公共卫生的影响需要认真考虑。在像癌症病因学这样充满活力的领域,我们发现格雷等人很奇怪。依赖于 1987 年的国际癌症研究机构 (IARC) 文件,该文件对任何化合物的致癌性数据的充分性做出了结论。在过去的 26 年里,对癌症生物学和病因学的理解取得了重大飞跃,我们认为非常需要 IARC 对有关特定农药与特定癌症之间关联的现有文献进行全面的科学审查。格雷等人。还争辩说,由私营化学公司和 EPA 进行的杀虫剂动物毒性测试已充分证明这些化合物不会对人类构成重大健康风险。尽管动物模型对于预测暴露于环境化学品后可能发生的人类毒性是绝对必要的,但它们不足以用于公共卫生监测和保护。这个问题在制药行业的药物开发过程中得到了充分的证明。事实上,人类药物开发经常受到临床试验中出现的不可预测的不利健康影响的阻碍,但临床前动物模型或人类细胞培养实验都无法预测(Sun 等,2012)。此外,环境毒物如砷在流行病学研究中已被证明对人类具有剧毒,但与毒性动物模型不一致(Kitchin 和 Conolly,2010 年)。使用人类细胞定量高通量筛选 (qHTS) 技术来识别导致体内反应预测的毒性途径和分子机制的新策略将在未来成为有价值的工具(Sun 等,2012)。格雷等人。声明:“与丰富的动物毒理学数据库相比,依靠最少数量的探索性分子研究来假设这些经过充分研究的化合物的致癌作用的替代机制似乎是公然的推测”,并且“需要认真考虑寻找新的毒性途径当前的大量理解和证明偏离既定原则是合理的。” 不幸的是,许多环境化学物质导致癌症的机制实际上是否遵循“公认的原则”,这一点尚不清楚。事实上,在简单的基因毒性测定或终生动物生物测定中发现为阴性的化学物质仍然可能通过多种潜在机制促进人类癌症的形成,包括表观遗传、内分泌干扰和促炎途径——这些都不依赖于基因毒性。这些机制是目前对致癌过程理解的重要方面(Schottefeld 和 Fraumeni,2006 年);他们当然不是“公然投机”。通过流行病学研究、分子流行病学和毒理学研究评估农药对人类健康的影响,以评估对人类重要的机制,这对于保障健康是必要的。在简单的基因毒性试验或终生动物生物试验中发现阴性的化学物质仍可能通过多种潜在机制促进人类癌症的形成,包括表观遗传、内分泌干扰和促炎途径——这些都不依赖于基因毒性。这些机制是当前对致癌过程理解的重要方面(Schottefeld 和 Fraumeni,2006 年);他们当然不是“公然投机”。通过流行病学研究、分子流行病学和毒理学研究评估农药对人类健康的影响,以评估对人类重要的机制,这对于保障健康是必要的。在简单的基因毒性试验或终生动物生物试验中发现阴性的化学物质仍可能通过多种潜在机制促进人类癌症的形成,包括表观遗传、内分泌干扰和促炎途径——这些都不依赖于基因毒性。这些机制是当前对致癌过程理解的重要方面(Schottefeld 和 Fraumeni,2006 年);他们当然不是“公然投机”。通过流行病学研究、分子流行病学和毒理学研究评估农药对人类健康的影响,以评估对人类重要的机制,这对于保障健康是必要的。这些机制是目前对致癌过程理解的重要方面(Schottefeld 和 Fraumeni,2006 年);他们当然不是“公然投机”。通过流行病学研究、分子流行病学和毒理学研究评估农药对人类健康的影响,以评估对人类重要的机制,这对于保障健康是必要的。这些机制是当前对致癌过程理解的重要方面(Schottefeld 和 Fraumeni,2006 年);他们当然不是“公然投机”。通过流行病学研究、分子流行病学和毒理学研究评估农药对人类健康的影响,以评估对人类重要的机制,这对于保障健康是必要的。
更新日期:2013-05-30
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