Toxic Responses Induced at High Doses May Affect Benchmark Doses

To derive reference points (RPs) for health-based guidance values, the benchmark dose (BMD) approach increasingly replaces the no-observed-adverse-effect level approach. In the BMD approach, the RP corresponds to the benchmark dose lower confidence bounds (BMDLs) of a mathematical dose–response model derived from responses of animals over the entire dose range applied. The use of the entire dose range is seen as an important advantage of the BMD approach. This assumes that responses over the entire dose range are relevant for modeling low-dose responses, the basis for the RP. However, if part of the high-dose response was unnoticed triggered by a mechanism of action (MOA) that does not work at low doses, the high-dose response distorts the modeling of low-dose responses. Hence, we investigated the effect of high-dose specific responses on BMDLs by assuming a low- and a high-dose MOA. The BMDLs resulting from modeling fictitious quantal data were scattered over a broad dose range overlapping with the toxic range. Hence, BMDLs are sensitive to high-dose responses even though they might be irrelevant to low-dose response modeling. When applying the BMD approach, care should be taken that high-dose specific responses do not unduly affect the BMDL that derives from low doses.

Application of benchmark analysis for mixed contaminant exposures: Mutual adjustment of two perfluoroalkylate substances associated with immunotoxicity

BackgroundDevelopmental exposure to perfluorinated substances is associated with deficient IgG antibody responses to childhood vaccines as an indication of depressed immune system functions. As this outcome may represent a critical effect of these substances, calculation of benchmark dose (BMD) results would be useful for standards setting to protect exposed populations against adverse effects. However, in the mixed exposure setting of most epidemiological evidence, the two major and inter-related substances associated with this adverse effect have shown similar benchmark results that raise concerns about possible confounding.MethodsWith the aim of better characterizing the immunotoxicity impact of the two major perfluorinated substances in the mixed exposures, we carried out BMD calculations on prospective data from two prospective birth cohort studies from the Faroe Islands with a total of 1,146 children. Exposure data included serum concentrations of perfluorooctane sulfonate and perfluorooctanoate at birth and at age 5 years and, as outcome parameters, the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7. We calculated the BMDs and their lower confidence bounds (BMDLs) and included mutual adjustment for the two compounds.ResultsThe BMDLs for the two immunotoxicants were of similar magnitude before and after adjustment. Both substances showed lower results for a logarithmic dose-response model, which also provided a slightly better fit than a linear dose model for both antibodies. We also used a broken curve shape that allowed a different slope below the median exposure. Postnatal exposure as represented by the age 5 serum concentration, showed a stronger association with the antibody outcomes than the prenatal exposure. Due to the correlation between the two immunotoxicants, the mutual adjustment resulted in elevated BMD results and p values. However, the BMDL values were virtually unchanged.ConclusionsAdjustment for co-exposure to another immunotoxicant increased the variance and the BMD values, but affected the BMDL values only to a negligible extent. These calculations are in accordance with an interpretation that, when two toxicants appear to affect an outcome to an almost equal degree and none of them is known to be solely responsible, the exposures should both be considered responsible and attract equal regulatory attention until further evidence shows otherwise.

When, not if: the inescapability of an uncertain climate future

Climate change projections necessarily involve uncertainty. Analysis of the physics and mathematics of the climate system reveals that greater uncertainty about future temperature increases is nearly always associated with greater expected damages from climate change. In contrast to those normative constraints, uncertainty is frequently cited in public discourse as a reason to delay mitigative action. This failure to understand the actual implications of uncertainty may incur notable future costs. It is therefore important to communicate uncertainty in a way that improves people’s understanding of climate change risks. We examined whether responses to projections were influenced by whether the projection emphasized uncertainty in the outcome or in its time of arrival. We presented participants with statements and graphs indicating projected increases in temperature, sea levels, ocean acidification and a decrease in arctic sea ice. In the uncertain-outcome condition, statements reported the upper and lower confidence bounds of the projected outcome at a fixed time point. In the uncertain time-of-arrival condition, statements reported the upper and lower confidence bounds of the projected time of arrival for a fixed outcome. Results suggested that people perceived the threat as more serious and were more likely to encourage mitigative action in the time-uncertain condition than in the outcome-uncertain condition. This finding has implications for effectively communicating the climate change risks to policy-makers and the general public.

Paraplegia and Paraparesis From Intrathecal Methotrexate and Cytarabine Contaminated With Trace Amounts of Vincristine in China During 2007

Purpose The production and administration of drugs used intrathecally requires special care to prevent contamination with neurotoxic agents. In 2007, we investigated a widespread outbreak of paraplegia and paraparesis among Chinese patients who received intrathecal drugs to identify the presumed contaminant and its source to prevent further cases. Patients and Methods We defined a case as onset from January 1 to October 31, 2007, of bilateral flaccid paraparesis or paraplegia or retention and incontinence of stool or urine, in a patient receiving intrathecal drugs. Using a retrospective cohort approach, we selected 12 hospitals from all hospitals that had reported cases. In these hospitals, we identified all 448 patients (including 107 cases) who received intrathecal chemotherapy or chemoprophylaxis in 2007. We calculated attack rates and Mantel-Haenszel adjusted risk ratios for intrathecal drug type and lot. Results All 12 hospitals used intrathecal methotrexate or cytarabine produced by one pharmaceutical plant. Only two lots of each drug were associated with cases. Lot-specific attack rates ranged from 42% to 100% (risk ratio, ∞; lower confidence bounds, 1.8 to 7.3). Vincristine production had immediately preceded production of the implicated lots on the same equipment. By using ultra performance liquid chromatography, we detected vincristine (0.28 to 18 μg) in unused vials from implicated lots of methotrexate and cytarabine. Conclusion Trace amounts of vincristine that contaminated intrathecal drugs caused a large outbreak of severe neurologic damage. Vincristine and other neurotoxic drugs should not be produced on any equipment that is also used for producing drugs that are to be administered intrathecally.

Lower Confidence Bounds for the Probabilities of Correct Selection

We extend the results of Gupta and Liang (1998), derived for location parameters, to obtain lower confidence bounds for the probability of correctly selecting thetbest populations(PCSt)simultaneously for allt=1,…,k−1for the general scale parameter models, wherekis the number of populations involved in the selection problem. The application of the results to the exponential and normal probability models is discussed. The implementation of the simultaneous lower confidence bounds forPCStis illustrated through real-life datasets.