How America became obsessed with BPA
Willhite’s critique of the paper’s Watchdog report on microwaveable plastic contatiners
A. The Journal Sentinel report states: “The amounts detected were at levels that scientists have found cause neurological and developmental damage in laboratory animals. The problems include genital defects, behavioral changes and abnormal development of mammary glands.”
Unfortunately, no publications from the toxicological literature were cited in the newspaper report but it appears the authors neglected the conclusions of the U.S. National Institute of Health’s review panel on bisphenol A (BPA). That panel report was convened by the Center for the Evaluation of Risks to Human Reproduction (CERHR) and it can be read in its entirety in Birth Defects Research (Part B) Volume 83, pages 157-395. This publication is readily available through the World Wide Web and in most university libraries. On the point about “developmental damage to laboratory animals”, the CERHR (2008) concluded:
- “Bisphenol A does not cause malformations or birth defects in rats or mice at levels up to the highest doses evaluated: 640 mg/kg-day (rats) and 1250 mg/kg-day (mice).
- Bisphenol A does not alter male or female fertility after gestational exposure up to doses of 450 mg/kg-day in the rat and 600 mg/kg-day in the mouse (highest dose levels evaluated).
- Bisphenol A does not cause prostate cancer in rats or mice after adult exposure at up to 148 or 600 mg/kg-day, respectively.
- Bisphenol A does change the age of puberty in male or female rats at high doses (~ 475 mg/kg-day).
- Rodent studies suggest that bisphenol A causes neural and behavioral alterations related to disruptions in normal sex differences in rats and mice (0.01 – 0.2 mg/kg-day).”
Therefore, the Journal Sentinel conclusion that prenatal BPA exposure in rodents causes ‘developmental damage’ cannot be supported from the available literature. The CERHR (2008) conclusion that rodent studies suggest changes in behavior associated with BPA exposure is based on studies that examined only a single dose level or that studied only one or two offspring per litter. Ordinarily, these studies examine a series of doses and examine all of the members of a litter. Of those that examined more than a single dose level, there was no dose-response relationship – a prerequisite to establishment of cause-and-effect. The studies are highly variable; in some the males were more sensitive, in others the females were more sensitive and in others there were no differences at all. When one takes into account the very efficient intestinal and liver detoxification of BPA after ingestion, it is not clear that any of the extremely small quantities of BPA (sometimes microgram per kilogram of body weight given to the animals in those studies) could survive the trip through the gut and the liver to make it to the brain. Since many of the changes reported are within the range of normal behaviors of these animals, it is not clear there was any actual adverse effect of BPA exposure at all.
Unfortunately, the behavioral and neurological database for BPA suffers from the fact that a rigorous neurobehavioral evaluation of BPA ingestion that meets current US EPA test guidelines has not been conducted. In the absence of sound behavioral studies that evaluate developmental landmarks, motor activity, a functional observational battery with evaluations of learning, memory and startle response, brain morphometry and in situ perfusion with routine histopathology taken together with measurements of free BPA concentrations in the brain (if any), it is likely that speculation concerning BPA and its influence on behavior as in the Journal Sentinel article will continue.
B. The Journal Sentinel report states: “The changes to the mammary glands were identical to those observed in women at higher risk for breast cancer” and it concludes, “But the Journal Sentinel identified several peer-reviewed studies that found harm to animals at levels similar to those detected in the newspaper’s [extraction] tests – in some cases as low as 25 parts per trillion.”
The Journal Sentinel report neglected to mention that all of the observations of changes in the female rodent mammary gland associated with BPA exposure were made after subcutaneous injections (e.g., Biology of Reproduction, Volume 65, pages 1215-1223, 2001; Congenital Anomalies, Volume 41, pages 187-193, 2002; Endocrinology, Volume 148, pages 116-127, 2007; Reproductive Toxicology, Volume 18, pages 803-811, 2004).
In contrast, the U.S. National Toxicology Program in 1982 [Carcinogenesis Bioassay of Bisphenol A (CAS No. 80-05-7) in F344 Rats and B6C3F1 Mice (Feed Study), Technical Report No. 215] concluded based on the results of lifetime BPA feeding studies that “there was no convincing evidence that bisphenol A was carcinogenic for F344 rats or B6C3F1 mice of either sex.” Given the irrefragable fact the animal evidence demonstrates a lack of any carcinogenic effect in both sexes (including that in the female mammary gland) based on well-designed and well-conducted lifetime oral exposure studies in at least two appropriate animal species and in the absence of other animal or human data suggesting a potential for carcinogenic effects, BPA can be considered not likely to be carcinogenic to human beings. Since there was no indication whatsoever of preneoplastic or neoplasic changes in the mammary gland of the rats and mice after lifetime ingestion of very high BPA doses (to as much as 148 milligrams/kilogram per day in rats and 1,900 milligrams/kilogram per day in mice), the suggestion that somehow BPA injection studies in rodents are directly relevant to human health is without empirical support.
It is now well established that 99% of a child’s BPA exposure is due to ingestion (Environmental Research, Volume 103, pages 9-20, 2007). It is noteworthy that the Journal Sentinel made no mention of actual human oral BPA exposures be they associated with migration from plastics (be they new or used) or from epoxy resins or from other environmental sources (including dust and soil collected in home vacuum cleaner bags). Rather, the Journal Sentinel made reference to only selected studies where the animals were exposed by subcutaneous injections.
In their concise review, Kang and associates (Toxicology Volume 226, pages 79-89, 2006) compiled many of the BPA exposure studies and concluded that human BPA exposure is less than 1 microgram per kilogram of body weight per day. In a 2008 biomonitoring study of BPA in 257 adults and 30 children (ages 5-6 years) living in the European Union, Volkel and coworkers (Toxicology Letters Volume 179, pages 155-162) found that the average daily BPA intake (over the years 2005 to 2008) was 0.03 microgram per kilogram of body weight per day. The highest BPA exposure was 0.233 micrograms per kilogram body weight per day. It is also noteworthy that the data from Volkel et al. (2008) are reasonably consistent with those from 5 other similar studies conducted in Japan and the United States.
Volkel et al. (2008) then calculated what is known as the “margin of exposure;” that is, one compares the Tolerable Daily Intake (a term used in the European Union) or the Acceptable Daily Intake (a term used by US regulatory authorities), to the actual human exposure. The margin of exposure is a ratio of these two amounts, and the higher it is the farther we are away from being exposed to the amounts that could cause adverse effects.
For the 95th percentile, the margin of exposure was 5000 and in the worst case (maximum exposure), the margin of exposure was 800. Since most authorities consider a10-fold exposure over the Tolerable Daily Intake (that is the human exposure is 10 or more times less than the Tolerable Daily Intake) to represent ‘minimal risk’, a BPA exposure between 800 and 5000 is normally interpreted as de minimis (trivial) risk.
Another way to compare the data is to contrast the daily doses consumed by the female rats and mice in the National Toxicology Program’s lifetime carcinogenesis bioassay with BPA to a daily human exposure of 1 microgram BPA per kilogram body weight per day, even though exposure is typically significantly lower (Kang et al., 2006). Using that ratio, the human daily oral exposure is 0.00005% to 0.00067% of that of rats and mice fed BPA each day for their entire life that failed to induce cancer of the mammary gland or other organs.
Much of the confusion evident in the Journal Sentinel article appears to stem from the fact that the authors failed to appreciate the differences in route of BPA exposure (ingestion vs. injection) and how the different routes of exposure influence the body’s metabolic detoxification and excretion of this substance. In the absence of understanding the role of biotransformation and elimination of BPA in relation to route of exposure, one can arrive at erroneous conclusions about risk to human health posed by trace levels of any material present in our environment.