Dispelling urban myths about default uncertainty factors in chemical risk assessment - Sufficient protection against mixture effects?

© 2013 Martin et al.; licensee BioMed Central LtdThis article has been made available through the Brunel Open Access Publishing Fund.Assessing the detrimental health effects of chemicals requires the extrapolation of experimental data in animals to human populations. This is achieved by applying a default uncertainty factor of 100 to doses not found to be associated with observable effects in laboratory animals. It is commonly assumed that the toxicokinetic and toxicodynamic sub-components of this default uncertainty factor represent worst-case scenarios and that the multiplication of those components yields conservative estimates of safe levels for humans. It is sometimes claimed that this conservatism also offers adequate protection from mixture effects. By analysing the evolution of uncertainty factors from a historical perspective, we expose that the default factor and its sub-components are intended to represent adequate rather than worst-case scenarios. The intention of using assessment factors for mixture effects was abandoned thirty years ago. It is also often ignored that the conservatism (or otherwise) of uncertainty factors can only be considered in relation to a defined level of protection. A protection equivalent to an effect magnitude of 0.001-0.0001% over background incidence is generally considered acceptable. However, it is impossible to say whether this level of protection is in fact realised with the tolerable doses that are derived by employing uncertainty factors. Accordingly, it is difficult to assess whether uncertainty factors overestimate or underestimate the sensitivity differences in human populations. It is also often not appreciated that the outcome of probabilistic approaches to the multiplication of sub-factors is dependent on the choice of probability distributions. Therefore, the idea that default uncertainty factors are overly conservative worst-case scenarios which can account both for the lack of statistical power in animal experiments and protect against potential mixture effects is ill-founded. We contend that precautionary regulation should provide an incentive to generate better data and recommend adopting a pragmatic, but scientifically better founded approach to mixture risk assessment. © 2013 Martin et al.; licensee BioMed Central Ltd.Oak Foundatio

Methyl methacrylate and respiratory sensitization: A Critical review

Methyl methacrylate (MMA) is a respiratory irritant and dermal sensitizer that has been associated with occupational asthma in a small number of case reports. Those reports have raised concern that it might be a respiratory sensitizer. To better understand that possibility, we reviewed the in silico, in chemico, in vitro, and in vivo toxicology literature, and also epidemiologic and occupational medicine reports related to the respiratory effects of MMA. Numerous in silico and in chemico studies indicate that MMA is unlikely to be a respiratory sensitizer. The few in vitro studies suggest that MMA has generally weak effects. In vivo studies have documented contact skin sensitization, nonspecific cytotoxicity, and weakly positive responses on local lymph node assay; guinea pig and mouse inhalation sensitization tests have not been performed. Cohort and cross-sectional worker studies reported irritation of eyes, nose, and upper respiratory tract associated with short-term peaks exposures, but little evidence for respiratory sensitization or asthma. Nineteen case reports described asthma, laryngitis, or hypersensitivity pneumonitis in MMA-exposed workers; however, exposures were either not well described or involved mixtures containing more reactive respiratory sensitizers and irritants.The weight of evidence, both experimental and observational, argues that MMA is not a respiratory sensitizer

Prognostic classification of Hodgkin disease in pathologic stage III, based on anatomic considerations

Fifty-two patients with pathologic stage III Hodgkin disease were studied in an effort to determine whether location of involved abdominal nodes influenced survival. Treatment consisted of total nodal radiotherapy with or without subsequent combination chemotherapy. Th initial radiation field was the “extended mantle,” which included supradiaphragmatic nodes, the splenic hilar area, and paraaortic nodes to the level of L2-L4. Subsequently, lower paraaortic and iliac regions were treated (“lower inverted Y”). Patients with disease limited to the spleen and/or splenic, celiac, or portal nodes (“anatomic substage” III1) had a more favorable 5-yr survival than did patients with involvement of paraaortic, iliac, or mesenteric nodes (“anatomic substage” III2): 93% versus 57%, respectively (p less than 0.05). The addition of combination chemotherapy to total nodal irradiation was associated with improved survival of patients in stage III2, but not of those in stage III1.</jats:p

Prognostic classification of Hodgkin disease in pathologic stage III, based on anatomic considerations

Abstract Fifty-two patients with pathologic stage III Hodgkin disease were studied in an effort to determine whether location of involved abdominal nodes influenced survival. Treatment consisted of total nodal radiotherapy with or without subsequent combination chemotherapy. Th initial radiation field was the “extended mantle,” which included supradiaphragmatic nodes, the splenic hilar area, and paraaortic nodes to the level of L2-L4. Subsequently, lower paraaortic and iliac regions were treated (“lower inverted Y”). Patients with disease limited to the spleen and/or splenic, celiac, or portal nodes (“anatomic substage” III1) had a more favorable 5-yr survival than did patients with involvement of paraaortic, iliac, or mesenteric nodes (“anatomic substage” III2): 93% versus 57%, respectively (p less than 0.05). The addition of combination chemotherapy to total nodal irradiation was associated with improved survival of patients in stage III2, but not of those in stage III1.</jats:p