Hattis D, Russ A, Goble R, Banati P, Chu M
Marsh Institute, Clark University, Worcester, MA 01610-1477, USA.
Risk Anal. 2001 Aug;21(4):585-99. doi: 10.1111/0272-4332.214137.
Part of the explanation for the persistent epidemiological findings of associations between mortality and morbidity with relatively modest ambient exposures to airborne particles may be that some people are much more susceptible to particle-induced responses than others. This study assembled a database of quantitative observations of interindividual variability in pharmacokinetic and pharmacodynamic parameters likely to affect particle response. The pharmacodynamic responses studied included data drawn from epidemiologic studies of doses of methacholine, flour dust, and other agents that induce acute changes in lung function. In general, the amount of interindividual variability in several of these pharmacodynamic response parameters was greater than the variability in pharmacokinetic (breathing rate, deposition, and clearance) parameters. Quantitatively the results indicated that human interindividual variability of breathing rates and major pharmacokinetic parameters-total deposition and tracheobronchial clearance-were in the region of Log(GSD) = 0.1 to 0.2 (corresponding to geometric standard deviations of 10(.1)-10(.2) or 1.26-1.58). Deposition to the deep lung (alveolar region) appeared to be somewhat more variable: Log(GSD) of about 0.3 (GSD of about 2). Among pharmacodynamic parameters, changes in FEV1 in response to ozone and metabisulfite (an agent that is said to act primarily on neural receptors in the lung) were in the region of Log(GSD) of 0.2 to 0.4. However, similar responses to methacholine, an agent that acts on smooth muscle, seemed to have still more variability (0.4 to somewhat over 1.0, depending on the type of population studied). Similarly high values were suggested for particulate allergens. Central estimates of this kind of variability, and the close correspondence of the data to lognormal distributions, indicate that 99.9th percentile individuals are likely to respond at doses that are 150 to 450-fold less than would be needed in median individuals. It seems plausible that acute responses with this amount of variability could form part of the mechanistic basis for epidemiological observations of enhanced mortality in relation to ambient exposures to fine particles.
对于在相对适度的环境空气颗粒物暴露情况下，死亡率和发病率之间持续存在的流行病学关联发现，部分解释可能是有些人比其他人更容易受到颗粒物诱发反应的影响。本研究收集了一个数据库，其中包含对可能影响颗粒物反应的药代动力学和药效学参数个体间变异性的定量观测数据。所研究的药效学反应包括从流行病学研究中获取的数据，这些研究涉及乙酰甲胆碱、面粉粉尘和其他可引起肺功能急性变化的物质的剂量。一般来说，这些药效学反应参数中几个参数的个体间变异性大于药代动力学（呼吸频率、沉积和清除）参数的变异性。从数量上看，结果表明人类呼吸频率以及主要药代动力学参数——总沉积和气管支气管清除——的个体间变异性处于对数几何标准差（Log(GSD)）为0.1至0.2的范围（对应几何标准差为10^0.1 - 10^0.2或1.26 - 1.58）。向深部肺组织（肺泡区域）的沉积似乎变异性稍大一些：对数几何标准差约为0.3（几何标准差约为2）。在药效学参数中，对臭氧和焦亚硫酸盐（一种据说主要作用于肺神经受体的物质）的反应中，第一秒用力呼气量（FEV1）的变化处于对数几何标准差为0.2至0.4的范围。然而，对作用于平滑肌的乙酰甲胆碱的类似反应似乎变异性更大（0.4至略高于1.0，具体取决于所研究的人群类型）。对于颗粒性过敏原也显示出类似的高变异性值。这种变异性的中心估计值以及数据与对数正态分布的紧密对应表明，第99.9百分位数的个体可能在比中位数个体所需剂量低150至450倍的剂量下产生反应。如此大的变异性导致的急性反应似乎有可能构成与环境细颗粒物暴露相关的死亡率增加的流行病学观察结果的部分机制基础。
