Dialkyl phosphates as biomarkers of organophosphates: The current divide between epidemiology and clinical toxicology

Abstract

Context. Organophosphate insecticides are widely utilized throughout the world. The cholinergic toxidrome, resulting from cholinesterase inhibition, is the clinically relevant endpoint in organophosphate poisoning. In recent years, urinary dialkyl phosphates (DAPs) have emerged as a common method of assessing exposure to organophosphates in epidemiological investigations. Using dialkyl phosphates as biomarkers of exposure to organophosphates, several recent epidemiological studies have reported associations with adverse health outcomes. The purpose of this article is to review the application and limitations of urinary DAPs as biomarkers of exposure to organophosphate insecticides. Methods. A literature search was conducted of the PubMed database, using keywords dialkylphosphate” and “dialkyl phosphate.” The scientific literature was reviewed to identify sources of dialkyl phosphate metabolites from in vivo metabolism of organophosphates, and as environmental degradation products. Epidemiological investigations were reviewed to summarize the use of use of DAPs as biomarkers in cross-sectional studies, occupational exposures, acute poisonings, and in health outcome studies. Emphasis was placed on the assessment of DAPs in the context of existing biomarker frameworks, as defined by the National Research Council. Studies were assessed for concurrent use of cholinesterase activity as a biomarker of effect, and whether a dose-response relationship could be determined between DAPs and cholinesterase depression or cholinergic effects. Results. Over 184 publications were identified, describing dialkyl phosphates and their use as biomarkers of exposure. The in vivo metabolism of organophosphates yields different DAPs, depending upon whether they undergo bioactivation or detoxification. The detection of urinary DAPs does not provide specificity with respect to the organophosphate from which they were derived, or their toxicological potency. Several recent studies documented the common presence of DAPs in residential environments and foods. Experimental studies support that DAPs have significant oral bioavailability, and undergo little to no metabolism prior to urinary excretion. Cross-sectional studies in multiple countries confirm that urinary DAPs are commonly detectable in the general population. No occupational studies were identified supporting a dose-response relationship between DAPs and significant cholinesterase inhibition. No occupational studies were identified supporting evidence of a threshold level of DAPs excretion at which clinical cholinergic signs or symptoms have been observed. Recent prospective epidemiological studies using DAPs as biomarkers have not concurrently assessed effects on cholinesterase activity, or conducted analyses that distinguish different DAPs that reflect bioactivation versus detoxification pathways. Discussion. There are numerous limitations to the use of DAPs as biomarkers of exposure. These include a lack of specificity with respect to the organophosphate from which they were derived, and a growing body of evidence that toxicologically irrelevant DAPs are commonly encountered in food and the environment. Substantial intra- and inter-day variability has been reported for dialkyl phosphate excretion in humans, which is problematic for studies that rely on single measurements to assess exposure. The toxicological distinction between different DAPs reflecting biomarkers of activation and detoxification processes has not been considered in some prospective epidemiological studies. A relationship between DAPs as biomarkers of exposure and the critical biomarker of effect, cholinesterase activity, has not been established. Conclusions. The science of exposure assessment using DAPs as biomarkers is not advancing, and this complicates the interpretation of epidemiological studies. At the current time, DAPs have very limited utility in clinical toxicology or in the risk assessment process for organophosphates. Until these limitations are addressed, the appropriate role of DAPs in the assessment of human health risks from organophosphates is unclear.