A critical evaluation of the creatinine correction approach: Can it underestimate intakes of phthalates? A case study with di-2-ethylhexyl phthalate

Abstract

The creatinine correction approach has been used to estimate daily intake for contaminants whose primary route of elimination is through urine. This method is challenged using the phthalate di-2-ethylhexyl phthalate (DEHP) as an example. An alternate prediction approach based on human experimental metabolism and urinary excretion data on DEHP was developed. This alternate model was developed from urine measurements of four metabolites of DEHP from two individuals partaking in different experiments, for up to 44 h after known exposures. Particular attention was paid to the changing ratios of the metabolites over time: they took a certain form when exposure was in the ''near'' (the past few hours) versus the ''distant'' (24 h or more) past. The creatinine correction approach was applied to measurements of the same four metabolites from 18 individuals in the National Health And Nutrition Evaluation Survey (NHANES) 2003/2004. The alternate model was also applied to these individuals, and the results were compared. Predictions using the two methods were similar or the creatinine correction predicted higher concentrations when the ratio suggested that the DEHP exposure was ''near'' in time, but the alternate approach predicted intakes that were an order of magnitude higher when the ratios suggested that the intake was ''distant''. As much as 25% of all NHANES measurements contain metabolites whose key ratio suggest that exposure was ''distant''. Uncertainties notwithstanding, the analysis in this article suggests that the creatinine correction approach should be used cautiously for DEHP and possibly other contaminants with similar exposure characteristics: rapid metabolism with metabolite urine elimination half-lives on the order of hours, and exposure patterns that may not be continuous and ongoing.

Exposure assessment issues in epidemiology studies of phthalates

“…It has been proposed that the ratio of MECPP to MEHHP could be an indicator of duration since time of DEHP exposure based on the differences in half-lives between the metabolites (Lorber et al 2011). Further, because MEHP is bioactive and subsequent phase II biotransformation produces the more hydrophilic oxidized metabolites (Barr et al 2003; Silva et al 2003), it has also been proposed that the ratio of MEHP to all DEHP metabolites (referred to as MEHP%) could serve as a phenotypic marker of individual susceptibility to DEHP exposure since it may represent a person’s relative efficiency to form the more hydrophilic and potentially less biologically active secondary metabolites (Hauser 2008; Meeker et al 2012).…”

A Longitudinal Study of Urinary Phthalate Excretion in 58 Full-Term and 67 Preterm Infants from Birth through 14 Months

“…It is still debated whether urinary concentrations of phthalate metabolites should be adjusted for creatinine (Lorber et al 2011) to correct for dilution. We did not use creatinine correction for the first 3 days because levels are elevated due to maternal contamination (Matos et al 1998).…”

Urinary phthalate metabolites in relation to biomarkers of inflammation and oxidative stress: NHANES 1999–2006

“…Another factor that likely contributes to the variability in MEHP% between individuals relates to sample timing if human exposure to DEHP is episodic. Since the oxidized DEHP metabolites have a longer biological half-life (10-15 hours) compared to MEHP (5 hours) (Lorber et al 2010), a higher MEHP% for an individual may also reflect that the person experienced a more recent DEHP exposure event compared to an individual with a low MEHP%. However, high reliability in urinary MEHP% within individuals over time was recently reported (Adibi et al 2008) which may provide support for underlying inter-individual differences in DEHP metabolism.…”