Identifying /Evaluating Sources Of Variability In Rodent

该项目的目标是识别和评估可能影响实验室研究中反应变异性的因素。例如，我们研究了相对于旧的NIH-07饮食，新的NTP-2000饮食对F344大鼠体重、生存和肿瘤发生的影响。我们发现，无论性别或饲养条件如何，饲喂NTP-2000日粮组的成活率显著高于饲喂NIH-07日粮组（p<0.05）。使用NTP-2000饮食还可以降低男女垂体瘤的发病率，降低男性肾上腺嗜铬细胞瘤和包皮腺肿瘤的发病率。接受NTP-2000饮食的动物，尤其是雄性，肾病的发病率和严重程度也有所降低。肾病严重程度的降低和垂体瘤的发生率的降低可能是与NIH-07饮食相比，接受NTP-2000饮食的大鼠存活率提高的主要因素。本研究的第二个目的是比较饲养研究控制组（分组饲养在悬挂式抽屉式聚碳酸酯笼中，并以糊状形式接受饲料）和吸入研究控制组（单独饲养在不锈钢铁丝网笼中，并饲喂颗粒饲料）的肿瘤发病率。这两个对照组在各种肿瘤的发生率上有显著差异（p<0.01），表明动物护理和饲养方案的差异可能影响F344大鼠的肿瘤发生。我们还评估了一系列文章中描述的对数线性外推模型，该模型可以证明阈值并解决与低剂量癌症风险外推相关的不确定性。我们指出了该模型的重大缺陷，即它(i)是一个本质上强制设置阈值的模型；（ii）假设控制响应是已知无误差的；（iii）忽略外推阈值估计的不确定性；（iv）主观地抛弃外推中的数据点，包括低剂量下可能重要的肿瘤反应；(v)即使所有剂量组都显示出高度显著的致癌作用，据称也能明确证明阈值；（六）据称可以明确证明少至两次剂量的阈值；（vii）在低剂量区域的某个未知点失效，可能远高于所声称的阈值剂量；（viii）明显低估了低剂量风险。由于这些原因，科学界采用这种对数线性外推模型进行化学致癌风险评估将是一个严重的错误。

The goal of this project is to identify and evaluate factors that may influence variability in response in laboratory studies. For example, we investigated the impact of the new NTP-2000 diet on body weight, survival and tumor occurrence in F344 rats relative to the older NIH-07 diet. We found that survival was significantly (p<0.05) higher in groups fed the NTP-2000 diet compared to the corresponding groups fed the NIH-07 diet, irrespective of sex or housing conditions. Use of the NTP-2000 diet was also associated with a decreased incidence of pituitary gland tumors in both sexes and decreased incidences of adrenal pheochromocytoma and preputial gland tumors in males. The incidence and severity of nephropathy was also reduced in animals receiving the NTP-2000 diet, especially males. The decreased nephropathy severity and the decreased incidence of pituitary gland tumors are likely the major factors contributing to the improved survival of rats receiving the NTP-2000 diet compared to those given the NIH-07 diet. A secondary objective of this study was to compare tumor incidences in feeding study controls (which are group housed in hanging-drawer-type polycarbonate cages and receive the diet in mash form) and inhalation study controls (which are individually housed in stainless steel wire mesh cages and are fed pelleted feed). These two control groups differed significantly (p<0.01) in the incidence of a variety of tumors, suggesting that differences in animal care and housing protocols may impact tumor occurrence in F344 rats. We also evaluated a log linear extrapolation model that has been described in a series of articles as a procedure that can demonstrate a threshold and resolve the uncertainies associated with low dose cancer risk extrapolation. We pointed out the significant shortcomings of this model, namely that it (i) is a model that essentially forces a threshold; (ii) assumes the control response is known without error; (iii) ignores the uncertainty of the extrapolated threshold estimate; (iv) subjectively discards datapoints from the extrapolation, including potentially important tumor responses at low doses; (v) purportedly can unequivocally demonstrate thresholds even when all dosed groups show highly significant carcinogenic effects; (vi) purportedly can unequivocally demonstrate thresholds with as few as two doses; (vii) fails at some unknown point in the low dose region, possibly well above the purported threshold dose; and (viii) demonstrably can significantly under-estimate low dose risk. For these reasons, it would be a serious mistake for the scientific community to adopt this log linear extrapolation model for chemical carcinogenesis risk assessment.