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Biomonitoring Studies Confirm Human Exposure to Bisphenol A is Very Low - Low Exposure Supports Low Risk to Human Health

May 4, 2005

Summary

Human biomonitoring data on bisphenol A (BPA) have been reported in a number of studies worldwide. These studies consistently indicate that human daily intake of bisphenol A is very low and likely to be in the range of 20-30 nanograms/kg-body weight/day for adults. These levels are about 1,000,000 times below the levels where no adverse effects on reproduction and development were observed in multi-generation animal studies. Similarly, these levels are about 400-2,000 times below lifetime daily intake levels set by government bodies in the US and Europe. Exposures below the lifetime daily intake levels are expected to have no adverse effect on health. Both comparisons indicate a substantial margin of safety between actual and safe exposure levels. Overall, the available biomonitoring data on bisphenol A supports the conclusion that exposure to bisphenol A from all sources poses no known risk to human health.

What is Biomonitoring?

Biomonitoring is a scientific technique for directly measuring human exposure to natural or synthetic substances. The technique involves analysis of human tissues or fluids such as blood or urine for the substance itself or for a biomarker that indicates exposure to the substance. (1) An important aspect of biomonitoring is that it can directly measure the amount of a substance in the body from all sources of exposure at a certain point in time. However, biomonitoring by itself does not provide information on the source, timing or health effects of the exposure.

Biomonitoring is not new. It was applied more than 100 years ago to monitor occupational exposure to chemicals such as lead or uptake of pharmaceutical compounds. In recent years biomonitoring has become more common due to lower laboratory costs and advances in analytical techniques that allow detection of very low levels of substances. A notable example is the biannual biomonitoring study on the US population conducted by the US Centers for Disease Control and Prevention (CDC), which currently includes more than 100 substances. (2)

How is Biomonitoring Data Used?

Public health scientists use biomonitoring data to establish reference ranges for exposure within a population, understand differences in exposure between different groups, and evaluate trends in exposure over time.

An important caution is that detecting a substance in a person's body does not by itself indicate that the exposure causes harm, only that the substance is present at that point in time. Sensitive analytical techniques increasingly allow detection of very low levels of many substances, but those same techniques do not provide any indication whether the detected substances have caused or could cause a health effect. (3)

However, when combined with toxicity information, direct measurements of exposure, such as biomonitoring data, are of particular value for assessing potential health risks from exposure to a substance. Information on exposure levels is a critical requirement for risk assessment, since health risks are a function of exposure level (i.e., "the dose makes the poison").

How is Biomonitoring for Bisphenol A Conducted?

Biomonitoring is most commonly conducted by analysis of blood or urine but, in principle, many other human tissues and fluids can be analyzed. For any substance, the most appropriate tissue or fluid is selected based on the chemical and physical properties of the substance and, in particular, the basic mechanisms by which the substance is processed in the body (i.e., absorption, distribution, metabolism and excretion). In general, substances that do not persist or accumulate in the body are most commonly measured in urine.

The mechanisms by which bisphenol A is processed in the body have been very well characterized by a variety of studies on laboratory animals and, most importantly, in human volunteer studies. (4) After ingestion, which is the most probable route of exposure for people, bisphenol A is readily absorbed and efficiently converted to a glucuronide metabolite as it passes through the intestinal wall and the liver. The metabolite, in which bisphenol A is chemically linked to a sugar molecule, is water soluble and is entirely excreted into urine by humans.

The lifetime of the glucuronide metabolite in the human body is quite short with a half-life less than 6 hours, which means that any bisphenol A exposure will be eliminated from the body within a day. Neither bisphenol A nor the metabolite accumulate or persist in the body. Because of the efficiency of the metabolic process, essentially all bisphenol A in the body is in the form of the glucuronide metabolite, which has been shown to be non-estrogenic and has no known biological activity. (5)

Based on the characteristics of bisphenol A in the body, biomonitoring studies are most appropriately conducted by analysis of urine, where bisphenol A is present in the form of the glucuronide metabolite. Because it is easier to measure bisphenol A itself, the glucuronide metabolite is usually hydrolyzed back to bisphenol A by treatment of urine samples with an enzyme before the analysis.

What Does Biomonitoring Data Tell Us About Human Exposure to Bisphenol A?

Recently published studies in which human urine samples were analyzed for bisphenol A indicate that exposure to bisphenol A is extremely low, in the range of 20-30 nanograms/kg-body weight/day. Included are two studies in which urine samples were collected over 24-hour periods. In one of these studies, the median level of bisphenol A excreted by 36 Japanese adult males was estimated as 1.2 micrograms/day. (6)This study also examined day-to-day variation by collecting 24-hour urine samples for 5 consecutive days for 4 males and 1 female. Although the median value was essentially the same at 1.3 micrograms/day, the study demonstrated variation between days and between individuals. A second study reported the average level of bisphenol A excreted by 11 Japanese males and 11 females, all adults, to be 1.68 micrograms/day. (7)

The amount of bisphenol A excreted in a 24-hour period is a good estimate of bisphenol A daily intake because of the short half-life of bisphenol A in the body. For an adult body weight of 60 kg, the typical bisphenol A daily intake estimated from 24-hour urine data is in the range of 20-30 nanograms/kg-body weight/day. Although single day intakes may be somewhat higher or lower than this range, the day-to-day variation demonstrated in one study suggests that this range is a reasonable estimate of average long-term daily intake for individuals and groups. Average long-term daily intake is the most appropriate intake value for risk assessment purposes.

A number of other studies have also analyzed spot samples of human urine for bisphenol A. Daily intakes can be estimated by multiplying bisphenol A concentration values (i.e., reported as micrograms BPA/liter urine or micrograms BPA/gram creatinine) by either a typical daily urinary volume (2 liters/day) or a typical daily creatinine excretion rate (1.2 grams/day). Using this technique, three recent Japanese studies indicate median daily intakes of 1.2 micrograms/day for 42 males, (8) 0.92 micrograms/day for 48 females, (9)and less than 2.0 micrograms/day for 56 pregnant women, (10), (11) each of which are very similar to the daily intakes directly measured from 24-hour urine samples.

Most recently, the CDC reported bisphenol A concentrations in spot urine samples from 394 adults in the US. (12) Based on a median concentration of 1.32 micrograms BPA/gram creatinine, the median daily bisphenol A intake can be estimated as approximately 1.6 micrograms/person/day, which indicates that human exposures to bisphenol A in the US and Japan are very similar.

Overall, the studies conducted in Japan and the US consistently indicate that typical long-term human exposure to bisphenol A is very low and likely to be in the range of 20-30 nanograms/kg-body weight/day.

What Does the Bisphenol A Biomonitoring Data Mean?

To put the biomonitoring data into perspective, it is helpful to compare typical daily intakes to acceptable daily intakes set by government bodies. These acceptable daily intakes are derived from toxicity studies to which conservative safety factors are applied to estimate lifetime exposure levels that are expected to be without adverse effects. Typical daily intake values can also be compared directly to doses that have been shown to cause no adverse effects in toxicity studies.

A typical daily intake of 25 nanograms/kg-body weight/day is about 1,000,000 times lower than levels where no adverse effects on reproduction or development were observed in multi-generation animal studies, which indicates a very large margin of safety. (13)

By application of safety factors, the US Environmental Protection Agency has set a Reference Dose of 50 micrograms/kg-body weight/day (14) and the European Commission's Scientific Committee on Food has set a Tolerable Daily Intake of 10 micrograms/kg-body weight/day. (15) In comparison, a typical daily bisphenol A intake of 25 nanograms/kg-body weight/day is 400-2,000 times lower, which also indicates a substantial margin of safety between actual and safe exposure levels.

Overall, the available biomonitoring data on bisphenol A indicates that actual human exposure to bisphenol A is far below levels that could cause adverse health effects and supports the conclusion that exposure to bisphenol A from all sources poses no known risk to human health.

 

1. For general information on biomonitoring, see http://www.biomonitoringinfo.org.

2. Information on the CDC biomonitoring program is available at http://www.cdc.gov/biomonitoring/.

3 For a general discussion on the significance of trace chemicals in the body, see "Traces of Environmental Chemicals in the Human Body: Are They a Risk to Health?" from the American Council on Science and Health at http://www.acsh.org/publications/pubID.195/pub_detail.asp.

4 "Metabolism and kinetics of bisphenol A in humans at low doses following oral administration", W. Völkel, T. Colnot, G. A. Csanady, et al., Chemical Research in Toxicology (2002), 15:1281-1287.

5 "In vitro and in vivo interactions of bisphenol A and its metabolite, bisphenol A glucuronide, with estrogen receptors alpha and beta", J. B. Matthews, K. Twomey, and T. R. Zacharewski, Chemical Research in Toxicology (2001), 14:149-157.

6 "Daily urinary excretion of bisphenol A", C. Arakawa, K. Fujimaki, J. Yoshinaga, et al., Environmental Health and Preventive Medicine (2004), 9:22-26.

7 "Development of analytical method for determining trace amounts of BPA in urine samples and estimation of exposure to BPA", T. Tsukioka, J. Terasawa, S. Sato, et al., Journal of Environmental Chemistry (2004), 14:57-63.

8 "Urinary bisphenol A and plasma hormone concentrations in male workers exposed to bisphenol A diglycidyl ether and mixed organic solvents", T. Hanaoka, N. Kawamura, K. Hara, and S. Tsugane, Occupational and Environmental Medicine (2002), 59:625-628.

9 "Measurement of bisphenol A in human urine using liquid chromatography with multi-channel coulometric electrochemical detection", K. Ouchi and S. Watanabe, Journal of Chromatography B (2002), 780:365-370.

10 A more accurate median value could not be estimated since BPA was below the detection limit for 39 of 56 samples. Consequently, the reported median of <2 micrograms/day overestimates actual exposure, which is likely to be comparable to or below the levels reported in other studies.

11 "Estimation of intake level of bisphenol A in Japanese pregnant women based on measurement of urinary excretion levels of the metabolite", K. Fujimaki, C. Arakawa, J. Yoshinaga, et al., Japanese Journal of Hygiene (2004), 59:403-408.

12 "Urinary concentrations of bisphenol A and 4-nonyl phenol in a human reference population", A. M. Calafat, Z, Kuklenyik, J. A. Reidy, et al., Environmental Health Perspectives (2005), 113:391-395.

13 "Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats", R. W. Tyl, C. B. Myers, M. C. Marr, et al., Toxicological Sciences (2002), 68:121-146.

14 See http://www.epa.gov/iris.

15 See http://europa.eu.int/comm/food/fs/sc/scf/out128_en.pdf. ()

 


 


   
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