Kinetically-derived maximal dose (KMD) confirms lack of human relevance for high-dose effects of octamethylcylotetrasiloxane (D4)
by:
Borgert CJ, Burgoon LD, Fuentes C
Borgert CJ, Burgoon LD, Fuentes C
Summary:
The kinetically-derived maximal dose (KMD) is the maximum external dose where kinetics remain unchanged relative to lower doses. Toxicity may differ qualitatively above versus below the KMD. This evaluation tests whether high-dose toxic effects of octamethylcyclotetrasiloxane (D4), a lipophilic silicone monomer, stem from kinetic overload. Chronic rat inhalation at doses 10,000-fold above human exposures causes mild respiratory, hepatic, renal, uterine, and fertility effects, mostly lacking human relevance due to rodent-specific mechanisms. Bayesian analysis with differential equations was applied to information from kinetic studies on D4 to build statistical distributions of plausible values of the Km and Vmax for D4 elimination. A set of Michaelis–Menten equations were generated to represent the slope function for the relationship between D4 exposure and blood concentration. The resulting Michaelis–Menten functions were investigated using a change-point methodology known as the “kneedle” algorithm to identify the probable KMD range. Analysis of the Michaelis–Menten elimination curve generated from those Vmax and Km values indicates a KMD with an interquartile range of 230.0–488.0 ppm, which is consistent with prior work indicating saturation of D4 metabolism at approximately 300 ppm. The results support the hypothesis that many adverse effects of D4 arise secondary to high-dose-dependent events, likely due to mechanisms of action that cannot occur at concentrations below the KMD. Regulatory methods to evaluate D4 for human health protection should avoid endpoint data from rodents exposed to D4 above the KMD range and future toxicological testing should focus on doses below the KMD range.
The kinetically-derived maximal dose (KMD) is the maximum external dose where kinetics remain unchanged relative to lower doses. Toxicity may differ qualitatively above versus below the KMD. This evaluation tests whether high-dose toxic effects of octamethylcyclotetrasiloxane (D4), a lipophilic silicone monomer, stem from kinetic overload. Chronic rat inhalation at doses 10,000-fold above human exposures causes mild respiratory, hepatic, renal, uterine, and fertility effects, mostly lacking human relevance due to rodent-specific mechanisms. Bayesian analysis with differential equations was applied to information from kinetic studies on D4 to build statistical distributions of plausible values of the Km and Vmax for D4 elimination. A set of Michaelis–Menten equations were generated to represent the slope function for the relationship between D4 exposure and blood concentration. The resulting Michaelis–Menten functions were investigated using a change-point methodology known as the “kneedle” algorithm to identify the probable KMD range. Analysis of the Michaelis–Menten elimination curve generated from those Vmax and Km values indicates a KMD with an interquartile range of 230.0–488.0 ppm, which is consistent with prior work indicating saturation of D4 metabolism at approximately 300 ppm. The results support the hypothesis that many adverse effects of D4 arise secondary to high-dose-dependent events, likely due to mechanisms of action that cannot occur at concentrations below the KMD. Regulatory methods to evaluate D4 for human health protection should avoid endpoint data from rodents exposed to D4 above the KMD range and future toxicological testing should focus on doses below the KMD range.