The Specificity of trans,trans- Muconic Acid as a Biological Indicator for Low Levels of Environmental Benzene

Abstract

trans, trans -Muconic acid (MA), a urinary ring-opened metabolite of benzene, is a newly proposed biological indicator of benzene exposure which should enable the assessment of low levels of exposure to this ubiquitous environmen tal pollutant. The presence of MA in the urine of non-occupationally exposed people is generally attributed to world-wide contamination of the environ ment by benzene (arising from such sources as smoking and other combustion, urban pollution from vehicles and maybe by food contamination). But, exami nation of the scientific literature reveals that a common food preservative and fungistatic agent, sorbic acid (SA), is also converted into MA, although in trace amounts. The permitted maximum concentration of SA in food ranges from 0.2 to 2 g·kg -1 and the acceptable daily intake (ADI-FAO/WHO) is 25 mg. kg -1 of body weight. The question, therefore, is whether the amount of MA excreted as a metabolite of SA can make a significant contribution to the total MA excreted. If so, the specificity of MA as a biological indicator for benzene exposure assessment is in doubt. Four experiments in 2 subjects were set up to try to clarify the effect on the urinary excretion of MA of the experimental ingestion of SA (2 doses of 447 and 44.7 mg); urine samples were collected, in fractions as voided, for 24 h before and 48 (or 60 h) after SA ingestion. The total amounts of MA excreted during the 24 h before ingestion of SA were respectively 79 and 34 mg in the 2 subjects; after ingestion of 447 or 44.7 mg of SA the total excretion of MA was at least respectively 20 and 2 times the background levels (when the single dose of SA was ingested) and at least 10 and 3 times (when the SA was given in divided doses). The elimination of MA after ingestion of SA was complete in 24 h; the peak concentrations always appeared in the first urine sample after the ingestion of the substance and they were more than 90 times and more than 3 times the basal levels respectively for a single ingestion of 447 and 44.7 mg of SA. The rate of biotransformation of SA into MA was, on average, 0.34 and 0.21 % in the 2 subjects; on the basis of these levels of biotransformation, it appears that 0.3-0.5 g of ingested SA would suffice to lead to excretion of 1 mg of MA, a quantity corresponding to that believed to derive from benzene exposure at levels greater than 1 ppm. Only in urine collected many hours after the last meal can a possible additive effect of MA from SA be ignored.

Assessment of the correlation between exposure to benzene and urinary excretion of t , t -muconic acid in workers from a petrochemical plant

“…A number of recent publications (Pezzagno and Maestri 1997;Renner et al 1999;Weaver et al 2000) has shown that at lower exposure levels the use of TTMA as a biomarker is complicated by the fact that it is also a metabolite of the food preservative, sorbic acid (SA). SA itself (the commercial product being the trans,trans-isomer) (E 200) and its salts: sodium (E 201), potassium (E 202), and calcium (E 203) sorbate have become the most commonly used preservatives in the food industry throughout the world over the past 30 years (Luck 1990).…”

“…If so, the specificity of TTMA as a biological indicator of benzene exposure assessment is in doubt. The special investigation by Pezzagno and Maestri (1997) shows that more than 75% of the TTMA of food origin is excreted within 6 h of ingestion. In order to avoid any confusion related to SA ingestion, all workers were advised 12 h before the investigation not to consume foods containing SA as an additive or anti-microbial agent: canned food (meat, fish), food emulsions (such as mayonnaise and salad dressings) and various beverages with SA content marked on the label.…”

“…TTMA -a urinary, ring-opened metabolite of benzene, has been shown to be a sensitive and specific biomarker for ambient benzene exposure, which should enable the evaluation of levels as low as approximately 0.5 ppm (Pezzagno and Maestri 1997;Weaver et al 2000).…”

Urinary Trans, Trans -Muconic Acid is Not a Reliable Biomarker for Low-level Environmental and Occupational Benzene Exposures

“…Although the International Program on Chemical Safety in 1993 reported that about 60% of workers are exposed to benzene at levels lower than 0.1 ppm and only 1% of them are exposed to levels higher than 10 ppm [1], workers in different industries and workplaces are among the higher-risk groups exposed to benzene.…”

Validation of Armadillo officinalis Dumèril, 1816 (Crustacea, Isopoda, Oniscidea) as a bioindicator: In vivo study of air benzene exposure

“…Whereas MA is not wholly specific (Vinci et al, 2012;Seow et al, 2012;Protano et al, 2010;Hoet Contents et al, 2009;Johnson et al, 2007;Weaver et al, 2000), S-PMA is a specific biological marker of benzene exposure (Tong et al, 2013;Seow et al, 2012;Hoet et al, 2009;Klauning and Kamendulis, 2004;Weaver et al, 2000;Pezzagno and Maestri, 1997), because it is unaffected by known confounding factors (Mandani et al, 2013;Fustinoni et al, 2012;Johnson et al, 2007;La Rocca et al, 2002;Pezzagno and Maestri, 1997).…”