Human Health & Safety >> Health Effects Research

Toxicology is the study of the harmful actions of agents on biological mechanisms. The toxicological effects of bisphenol A are well understood. One of the most extensively tested materials in use today, BPA exhibits toxic effects only at very high levels of exposure.

Toxic levels of BPA exposure result in weight loss in laboratory animals with other effects related to the weight loss as a consequence. There are no known risks from environmentally relevant levels of exposure to bisphenol A.

Key Toxicological Research
Conclusions of Key Toxicological Research
Subchronic and Chronic Toxicity

Key Toxicological Research

Bisphenol A (BPA) has been used safely as an industrial chemical for over 40 years. The toxicology of BPA has been extensively studied by industry, government and academic research groups in short and long term animal tests, including several reproduction studies, multi-generation exposure studies and a cancer bioassay, all of which are part of the open scientific literature. Importantly, none of the validated research suggests that BPA would cause adverse effects from exposure through consumer products or normal industrial production and use. Environmental and product-related exposure levels are anticipated to be well below any anticipated effect level.

Several conclusions in this toxicology summary deserve highlighting. In reproductive and developmental toxicity tests, no effects were seen in the offspring except when the dose was so high as to be maternally or systemically toxic. The multi-generation exposure studies show no treatment-related effects in any generation at exposure levels below those that were toxic to the parents. The short and long term animal studies show no treatment-related carcinogenesis or other pathology of the mammary gland or other reproductive organs of any species or sex. These observations support the conclusion that BPA did not produce estrogen-like effects in these studies.

This toxicity profile recommends the value of 50 mg/kg/day as the appropriate level for use in risk assessment of human exposures. This is the value that has been selected by the U.S. Environmental Protection Agency as a basis for calculating a reference dose for BPA. It is not clear how the special experimental systems looking at estrogenic activity relate to human health. As a result, these studies are reviewed and summarized in this web site, but were not used to estimate an effect level for BPA.

Conclusions of Key Toxicological Research

The toxicology of bisphenol A (BPA) has been extensively studied over the past several decades. Some studies have focused on the potential of BPA to act as an estrogen. These studies have shown that BPA possesses estrogenic activity in special experimental systems, however, it is not yet clear how relevant these studies are to human health. Thus, the use of these studies in estimating the NOEL for the toxicity of BPA is inappropriate at this time.

More importantly, there has been extensive investigation of the potential for BPA to produce reproductive and developmental toxicity, which are two possible manifestations of estrogenic effects. Based on the results of these studies, BPA should not be considered a selective reproductive or developmental toxicant. Some of the effects observed at dose levels sufficiently high to produce maternal toxicity included decreases in the live pup weight, the number of live pups/litter, the percentage of pups born alive and the postpartum dam weights (875 mg/kg/day). Some decreases in reproductive organ weights or the percent of motile sperm and/or sperm concentration were observed in males or the offspring of dams treated with BPA at doses producing either maternal toxicity and/or generalized systemic toxicity. The lowest NOEL when considering all studies for maternal or fetal effects was 50 mg/kg/day (Table 1 and Table 2).

The key studies of the subchronic and chronic toxicity of BPA have shown a lower body weight as a principal effect of BPA treatment for both rats and mice. The study of longest duration was the chronic bioassay conducted by the National Toxicology Program (NTP, 1982). The lowest observed effect level for this decreased body weight was for rats receiving 1000 ppm in the diet (50 mg/kg/day). Although a NOEL for these effects was not established in this study, the NOEL is probably not far below the LOEL of 50 mg/kg/day based on the results of the subchronic studies conducted by NTP. Since 50 mg/kg/day was also the lowest estimated NOEL for maternal and fetal effects in reproduction and developmental toxicity studies, this value is appropriate for use in risk assessment of human exposure.

Subchronic and Chronic Toxicity

In a two-week inhalation study, rats were exposed to 10, 50 or 150 mg/m³ of BPA aerosol for 6 hr/day for nine exposures. A very slight decrease (about 5%) in body weight gains of male rats exposed to 150 mg/m³ was observed. Microscopic changes, indicative of slight irritation, were observed in the anterior portion of the nasal cavity of rats exposed to 50 or 150 mg/m³ (Nitschke et al., 1985).

This study was followed by a 13-week inhalation study (6 hr/day, 5 day/week) where very slight to slight alterations of the upper respiratory tract were observed in rats exposed to 50 or 150 mg/m³ (Nitschke et al., 1985). The lesions were described as very slight to slight hyperplasia of the stratified squamous epithelium, respiratory epithelium and very slight to slight inflammation of the underlying submucosa. These changes were consistent with an adaptive response following a slight irritation of the upper respiratory tract. Examination of rats allowed to recover for 12 weeks following exposure to 150 mg/m³ indicated that the changes were fully reversible. Slight stress-related effects (decreased body weight, perineal soiling from urine and porphyrin-like material around the nose and eyes) were observed at all concentrations of BPA, although food consumption was not decreased. Terminal body weight of male rats at all exposure levels were not statistically different from control values, whereas the terminal body weight of females exposed to 140 mg/m³ was statistically decreased from controls (~11%). Except for decreased body weight of male rats exposed to 150 mg/m³ (although not statistically significant at ~6% decrease) these stress-related effects disappeared quickly following cessation of exposure. Enlarged ceca were observed in rats necropsied the day after the final exposures to 50 or 150 mg/m³ but were not present in rats sacrificed 12 weeks later. Enlarged ceca were most likely the result of ingestion of BPA due to grooming and/or clearance from the respiratory tract. The No Observed Effect Level (NOEL) in this study was 10 mg/m³, based on the slight to very slight histopathological alterations observed in the upper respiratory tract.

Particle size measurements indicated the majority of the solid aerosol particles generated in this study were in the respirable range (range 1.5 to 5.2 microns depending on the method used). Assuming 100% absorption of the inhaled BPA and respiratory minute volume of 0.8 liters/kg/min (Costa and Tepper, 1988), these exposures are calculated to be equivalent to doses of approximately 43,13 and 3 mg/kg/day for the 150, 50 and 10 mg/m³ exposure levels respectively. However, due to the effectiveness of the upper respiratory tract in removing dusts, it should be recognized that the dose which was delivered to the target organ (i.e.: the upper respiratory tract) in this study was likely to be significantly greater on a tissue weight basis than the dose calculated to be "systemically" available. Hence the use of systemic dose of 3 mg/kg/day as the NOEL for risk assessment for routes of exposure other than inhalation is inappropriate.

A 90-day dietary study in dogs at dose levels of 0, 1000, 3000 or 9000 ppm in the diet (0, 25, 75 or 225 mg/kg/day) resulted in an increase in relative liver weight at the highest dose level (Wazeter and Goldenthal, 1976). Tissues from dogs receiving 9000 ppm of BPA in the diet were examined histopathologically, there were no treatment-related effects. The NOEL in this study was 75 mg/kg/day.

Studies conducted by the National Toxicology Program (NTP) in preparation for a cancer bioassay found that oral doses in excess of 1000 ppm BPA in the diet caused depressed weight gain (18% and 10% in males and females, respectively). No effect on body weight was found at 500 ppm BPA in the diet. Hyaline masses were found in the urinary bladder lumen of all dosed male rats (250 ppm was the lowest dose tested) and multinucleated giant hepatocytes were also observed in male mice in a dose-related manner. Cecal enlargement (without histologic alterations) was noted at all dose levels in rats, with the exception of females at 250 ppm (dose levels ranged from 250 to 4000 ppm). This study is superceded by a NTP cancer bioassay, a study of longer duration (NTP, 1982).

In the NTP bioassay, rats were fed diets containing 1000 or 2000 ppm BPA, male mice were fed diets containing 1000 or 5000 ppm BPA and female mice were fed diets with 5000 or 10,000 ppm BPA for 103 weeks. There was "no convincing evidence that BPA was carcinogenic for F344 rats or B6C3F1 mice of either sex" (NTP, 1982)

At 1000 and 5000 ppm, there was an increase in the number of multinucleated giant hepatocytes in male mice. This effect was not considered adverse. Male mice at 5000 ppm and female mice at 5000 and 10,000 ppm had reduced body weights. Feed consumption could not be accurately determined for mice. The NOEL for mice was considered to be 1000 ppm or 130 mg/kg/day based on a food factor of 0.13.

Starting at 5 weeks, all treated groups of rats had reduced body weights, as compared to controls although feed consumption was not statistically reduced until the 12th week of exposure. The NTP report suggests that since feed consumption for females was only 70-80% that of controls and about 90% of controls for males throughout most of the study, the reduced mean body weight gain may have been due to reduced feed consumption. Nevertheless, in the Integrated Risk Information System (IRIS) document reviewing BPA, the U.S. Environmental Protection Agency (U.S. EPA) states that the reduced body weight in rats was considered to be a direct adverse effect of BPA in the diet.

There were no other effects in rats which were believed to be treatment-related including histopathological changes in any organ or tissue. Specifically, there was no treatment-related carcinogenesis or other pathology of the mammary gland or other reproductive organs of either species or sex. These observations support the conclusion that BPA did not produce estrogen-like effects in these studies. The LOEL for body weight decreases in rats was 1000 ppm which was equivalent to 50 mg/kg/day. Although a NOEL for these effects was not established in this study, the NOEL is probably not far below the LOEL of 50 mg/kg/day based on the results of the subchronic studies conducted by NTP. For risk assessment purposes, a dose level of 50 mg/kg/day in rats was selected by the U.S. EPA as a basis for calculating the reference dose (RfD), based on the results of the NTP carcinogenesis bioassay.