SCIENCE BOARD TO THE FDA DRAFT OCTOBER 31, 2008 FDA report on bisphenol A

[Guest guest]

This is important stuff! I'd suggest printing this out - then taking your time to absorb all the information here! If your child has a good doctor, he/she should be interested in reading this . . . and in knowing that your child may have been exposed to extra hits of BPA that crossed the placenta and, possibly through nursing because of breast implants.Rogene

SUBMITTED TO: SCIENCE BOARD TO THE FDA DRAFT

OCTOBER 31, 2008 Link > FDA report on bisphenol A ============================================================== http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4386b1-05.pdf FDA SCIENCE BOARD SUBCOMMITTEE ON BISPHENOL A SCIENTIFIC PEER-REVIEW OF THE DRAFT ASSESSMENT OF BISPHENOL A

FOR USE IN FOOD CONTACT APPLICATIONS

MARTIN

A. PHILBERT, PH.D. (CHAIR,

MEMBER, SCIENCE BOARD) PROFESSOR

OF TOXICOLOGY & SENIOR

ASSOCIATE DEAN FOR RESEARCH UNIVERSITY

OF MICHIGAN

SCHOOL OF PUBLIC HEALTH

GARRET

FITZGERALD, M.D. (MEMBER,

SCIENCE BOARD) Professor

of Pharmacology & Chair University

of Pennsylvania School of Medicine

PHILIP

J. BUSHNELL, PH.D. Research

Toxicologist Neurotoxicology

Division National

Health and Environmental Effects

Research Laboratory Office

of Research and Development,

USEPA

ANTONIA

M. CALAFAT, PH.D. Lead

Research Chemist

National Center for Environmental Health Centers

for Disease Control and Prevention

HOWARD

HU, M.D. Professor

of Environmental Health Sciences & Chair University

of Michigan

School of Public Health

HOWARD

ROCKETTE, PH.D. PROFESSOR

OF BIOSTATISTICS & CHAIR UNIVERSITY

OF PITTSBURGH

SCHOOL OF PUBLIC HEALTH

JOHN

J. VANDENBERG, PH.D. ASSOCIATE

DIRECTOR FOR HEALTH

NATIONAL CENTER FOR ENVIRONMENTAL ASSESSMENT OFFICE

OF RESEARCH AND DEVELOPMENT, USEPA

SUBMITTED

TO: SCIENCE

BOARD TO THE FDA DRAFT

OCTOBER 31, 2008

CONTENTS

EXECUTIVE SUMMARY

3

CHARGE QUESTIONS AND FINDINGS

5

SUMMARY

13

ACKNOWLEDGEMENTS

14

LITERATURE CITED

14

ABBREVIATIONS

15

APPENDIX 1: PUBLIC MEETING NOTICE

16

APPENDIX 2: INVITED PANEL ROSTER

17

EXECUTIVE SUMMARY PROCESS The Science Board provides advice

primarily to the Commissioner of the USFDA and other appropriate officials on

specific complex and technical issues as well as emerging issues within the

scientific community. This temporary Subcommittee was established by the

Science Board and consists of two members of the Science Advisory Board and

five scientists drawn from academia and government agencies. The focus of this

Subcommittee is the scientific peer-review of the draft assessment prepared by

the FDA of bisphenol A for use in food contact applications. Members of the

subcommittee were selected by the Science Board for their expertise in

scientific disciplines relating specifically to the issues assessed in the FDA

draft safety assessment (http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-0038b1_01_02_FDA%20BPA%20Draft%20Assessment.pdf).

It is the purpose of the Subcommittee to provide advice and make preliminary

recommendations regarding the FDA draft safety assessment for subsequent action

by the full Board. A public meeting (Appendix 1) was held on September

16, 2008 at the Rockville Hilton at which the Subcommittee received from FDA

(Drs. Tarantino, Baily and Twaroski) a review of the process and scientific

methodologies employed in preparing the draft safety assessment of bisphenol A.

Dr. Bucher, Deputy Director of the National Toxicology Program (NIH-NIEHS)

presented the approach used by the NTP in arriving at their own assessment of

the safety of bisphenol A (i.e., NTP Brief). The final formal oral presentation

by Dr. Frederick vom Saal (University of Missouri-Columbia) provided the

Subcommittee with an overview of the conclusions of the Chapel Hill Bisphenol A

Expert Panel and of the areas in which that Panel differed from the FDA in its assessment

of the toxicity and potential risks from exposure to bisphenol A. Open public

hearings were followed by discussion between the Subcommittee and an invited

Panel that focused on interpretation of BPA research studies and data gaps

related to the draft safety assessment (Appendix 2). SPECIFIC FINDINGS OF THE

SUBCOMMITTEE Bisphenol A is present in food contact applications

resulting in dietary exposure of BPA to infants, children and adults. The

Subcommittee agrees with the focus of the draft assessment on dietary exposures

to children, because they are likely to have both greater exposures and

susceptibility than adults as a function of food consumption patterns,

metabolism, vulnerability of developing systems and other factors.

Nevertheless, it is the opinion of the Subcommittee that the FDA assessment

would be strengthened by considering cumulative exposures and differential risk

in neonates. The draft FDA exposure assessment has important

limitations including that it lacks an adequate number of infant formula

samples and relies on mean values rather than accounting for the variability in

samples. The draft FDA report does not articulate reasonable

and appropriate scientific support for the criteria applied to select data for

use in the assessment. Specifically, the Subcommittee does not agree that the

large number of non-GLP studies should be excluded from use in the safety

assessment. • Consistent and credible criteria for study inclusion,

recommended by the Subcommittee, would be to use those studies that are judged

as “adequate†by CERHR in the FDA hazard, dose-response and safety

assessment of BPA. In addition, several studies of effects of BPA on adult

humans and animal species that were published after the draft assessment was

finished should be considered for inclusion in the final assessment. • The Subcommittee finds that the assessment

lacks an adequate characterization of uncertainties in its estimates of both

exposure and effects. • The weight-of-the-evidence, including studies

identified by CERHR as adequate and having utility, provides scientific support

for use of a point of departure substantially below (i.e., at least one or more

orders of magnitude lower than) the 5 mg/kg bw/day level selected in the draft

FDA assessment. • Coupling together the available qualitative

and quantitative information (including application of uncertainty factors)

provides a sufficient scientific basis to conclude that the Margins of Safety

defined by FDA as “adequate†are, in fact, inadequate. CHARGE QUESTIONS AND FINDINGS 1. DOES THE ASSESSMENT REPORT OBJECTIVELY AND

TRANSPARENTLY IDENTIFY THE DATA AND METHODOLOGY USED, EXPLAIN HOW DATA WERE

SELECTED, AND IDENTIFY WHAT CRITERIA WERE USED TO DETERMINE THE SUITABILITY OF

THE DATA? DOES THE REPORT IDENTIFY THE SCIENTIFIC SUPPORT FOR THESE CRITERIA

AND METHODS? The

draft FDA Assessment of Bisphenol A for Use

in Food Contact Applications identifies the data and methods used to

develop an exposure assessment and a toxicological profile. The exposure

assessment and qualitative and quantitative information from the toxicological

profile are brought together in the Margins of Safety section of the draft

report to support conclusions as to the safety of food contact applications. Exposure Assessment: The exposure assessment is focused on food contact applications

only and does not consider the potential cumulative and interactive effects of

non-food contact exposures to BPA. Thus, this approach to assessing the risk of

exposure to BPA is intrinsically limited by its use of data from food contact

sources alone. On this point, FDA decided a

priori to leave out biomonitoring studies that could have shed light

on cumulative exposures and inter-individual variability in internal exposure.

Furthermore, the updated exposure assessment itself was limited both in size

(14 cans of infant formula), geographical and temporal distribution, and thus

did not adequately account for variability in potential exposures, which the

invited Panel (September 16, 2008 public meeting) noted could be very large.

Inter-individual differences in systemic internal exposure following a

standardized exposure to environmental BPA were not taken into account. Table 1

and the accompanying text portray a reasonable approach to estimate

age-specific BPA exposure, but the data are point estimates (e.g., a mean of

2.5 ppb BPA in formula from epoxy can coatings is used rather than a 95th

percentile [not provided] or the maximum value of 6.6 ppb from a sample of 14

cans). Other assumptions are not well supported (e.g., that by 12 months of age

a high percentage of infants have stopped consuming liquid formula and that PC

bottles are not sterilized for infants above 2 months of age) or addressed

(e.g., that microwave heating of formula in infant bottles may alter BPA

exposures). Arguments that the exposure estimates in

Table 1 are conservative (i.e., represent likely maximum values, rather than

averages) are provided in the FDA Draft. These arguments provide some

reassurance; nevertheless, the approach would be strengthened by (1) including

a wider range of samples for estimating BPA content in food products; (2) using

distributions of data values (rather than point estimates to describe

exposure); (3) a sensitivity analysis for data values without distributions;

and (4) demographic information to determine the numbers of individuals likely

to be exposed at each estimated concentration which would yield a more robust

basis for informing the safety assessment by producing characterizations such

as “5% of children < 1 y.o. are exposed to BPA from food contact above

[xx] μg/kg bw/dayâ€. Toxicological Profile: Criteria for selection of data are mentioned in the Toxicological

profile section, and a link to the FDA ‘Redbook 2000’ protocols is

provided. However, the criteria themselves are not given in the assessment,

except by mention of characteristics that disqualified studies from

consideration. In addition, the summary data tables in Appendix 1 and the

reviews of selected studies in Appendix 2 list study characteristics that were

cause for excluding studies from the assessment. A clearer and more specific

description of the criteria and decision rules for acceptance for both exposure

and effects studies would strengthen the assessment. For example, was a small

sample size considered an equivalent limitation for both positive studies

(where statistical power is not as much of a concern) and negative studies? The

logic required to proceed from listing study limitations to justification for

exclusion is more complex than the draft report would suggest. The Subcommittee

finds that the draft FDA report does not articulate reasonable and appropriate

scientific support for the criteria and methods employed in the draft

assessment and the Subcommittee does not agree that the large number of non-GLP

studies should be excluded from use in the safety assessment. As

shown in Appendix 2, the scientific evaluation and utility of studies is

summarized for several organizations (FDA, CERHR, EU RAR, EFSA). The draft FDA

report dismisses many studies that were judged by the CERHR as being

“adequate†[in terms of scientific strength] and of either

“limited†or “high utilityâ€[1,2]. The exclusion of studies judged by CERHR as adequate

and of high utility diminishes the weight of evidence judgments on hazard,

dose-response and safety of BPA food contact applications. The Subcommittee

finds that consistent and credible criteria for study inclusion would include accepting

those studies judged by CERHR as ‘adequate’ and of ‘high

utility’ as directly relevant to the FDA hazard, dose-response and safety

assessment. Those studies judged by CERHR as “adequate†and of

“limited†utility also provide useful information on the potential

hazards posed by exposure to BPA. 2. ARE UNCERTAINTIES IN THE ASSESSMENT OBJECTIVELY AND

TRANSPARENTLY IDENTIFIED AND CHARACTERIZED? Uncertainty

has both qualitative aspects (e.g., are the correct studies identified, are the

studies correctly interpreted) and quantitative aspects (e.g., are quantitative

data fully displayed, analyzed and communicated). Assumptions regarding the

conclusions of the assessment are provided that suggest uncertainties, but they

are not systematically presented as uncertainties. For example, the assessment

discusses ranges of exposure values but does not adequately quantify the

uncertainties associated with the estimates of exposure that are used to

determine the margins of safety. Rather than appropriately characterizing the

sampling variability within the FDA samples used to obtain exposure estimates,

and the estimates of exposure given by others, the document appears to appeal

to a set of assumptions based on scenarios related to packaging and usage

practices that the FDA feels are conservative. Uncertainties

regarding potential effects of BPA on neuro-developmental, prostate, mammary

gland and acceleration of puberty health endpoints are described qualitatively,

but no attempt is made to quantify or characterize those uncertainties. A

similar ambiguity exists with the limited available information that indicates

a role for BPA in the disturbance of some gender-dependent distinctions among

neurobehavioral phenotypes, e.g., the ablation of sexual dimorphism in open

field anxiety. Uncertainty regarding the selection of critical studies (e.g.,

the exclusion of studies judged by CERHR as adequate and of limited or high

utility) and the critical effect (e.g., neurobehavioral, prostate) is not

provided since the other studies are dismissed, yet such a discussion of

uncertainty is an essential element to informed decision making. The

Subcommittee finds that this is a major omission in the characterization of

uncertainty. Within

the section on Margins of Safety is the statement “A MOS higher than the

relevant UF indicates that the margin of safety is

“adequateâ€â€. The margin of safety (MOS) analysis compares the

NOAELs from the Tyl studies to age-stratified estimates of exposure[3,4]. This analysis assumes

“typical†uncertainty factors of 10 for intra-species variability

and inter-species variability for reversible effects (combined UF = 100); an

additional factor of 10 is applied for irreversible reproductive or

developmental effects, yielding a combined UF of 1000. A further factor of 10

for “systemic†toxicity from less-than-chronic exposure is also

used to extrapolate to chronic exposure. The combined UF is then stated to be

103 = 1,000, when it appears that with four areas of uncertainty it should be

greater than 1,000. This paragraph requires clarification including a more

complete discussion of the basis for selection of uncertainty factors (see, for

example, how EPA discusses uncertainty factors in recent IRIS assessments

www.epa.gov/iris). 3. ARE THERE ADDITIONAL SCIENTIFIC/ TECHNICAL STUDIES

RELEVANT TO THE ENDPOINTS EXAMINED AND THE ROUTE OF EXPOSURE THAT SHOULD HAVE

BEEN CONSIDERED? The

draft assessment considered, but rejected for various reasons, a number of

potentially relevant studies as described in the Appendices. The Subcommittee

finds that the CERHR evaluated studies in an appropriate manner and this

evaluation can provide a consistent and coherent basis for FDA evaluation. The

studies identified by CERHR as “adequate†should be considered as

alternatives for the qualitative and/or quantitative assessment in the body of

the assessment. In addition, consideration should be given to several studies

of effects of BPA on adult humans and animal species that were published after

the assessment was finished or that were identified by the Subcommittee, as

described below. (1) An

epidemiologic study that correlated biomonitoring data, e.g., urinary BPA

levels, with the prevalence of several diseases in humans should be examined to

guide experimental investigation of the BPA hazard to adult humans using animal

models to shed light on the biological plausibility of the associations that

were observed[5]. Limitations of

this study are recognized, such as (i) the cross-sectional nature of the study

(exposure did not precede the development of disease); (ii) the uncertainty as

to whether the single measurements of BPA levels in urine could adequately

represent chronic BPA exposure; (iii) the lack of internal consistency amongst

signals of chronic toxicity – i.e., there was a signal for

“coronary heart disease†[defined only by history] but no signal

with respect to effects on lipids or blood pressure or stroke and (iv) the

uncertain plausibility for an association with diabetes, as reflected by the

biphasic in vitro relationships with adiponectin and antioxidant enzyme levels;

the absence of any insulin clamp/BPA data in any species and the generally weak

evidence of insulin resistance (3 out of 4 estimates of HOMA). Nevertheless,

given the nature of the investigation and the well-recognized research value of

the study population (NHANES), the study’s findings are of concern, and

the Subcommittee concludes that consideration of this study is warranted. (2) An experimental

study in monkeys that showed that BPA blocked estrogen-mediated synaptogenesis

in hippocampus[6] confirms effects

previously reported from this group in adult rodent models[7]. It is recognized that feeding

estradiol chronically to ovarectomized animals may not simulate the effects of

phasic alterations in endogenous insulin and that a functional phenotype has

not been related directly to the hippocampal phenotype. Nonetheless, these

studies deserve consideration because of the significance of the effect and

consistency across species. The single dose of BPA used in the monkey study and

the subcutaneous route of administration will complicate its utility in any

risk assessment, however. (3) A

2007 study in mice published in the Proceedings of the National Academy of

Sciences on the impact of maternal exposure to BPA on DNA methylation at

metastable loci with resultant changes in offspring phenotype deserves

consideration, even though the study was not designed to ascertain

dose-response relationships, in so far as stable epigenetic changes during

early life are emerging as a major potential mechanism for the development of

adult chronic disease(8). (4) A

study summarizing the FDA Infant Feeding Practices Study was reported by Fein

SB and Falci, CD[9]. This report

of a national longitudinal study of food handling practices for infants at 2, 5

and 7 months of age, found that a large percentage of mothers heat baby bottles

with formula in a microwave oven. The effect of microwave heating on BPA release

from baby bottles is an unexplored limitation in the FDA assessment. Finally, although the Subcommittee can appreciate the

FDA's decision to focus the quantitative risk assessment process on the large

Tyl studies, it disagrees with the decision by FDA to dismiss many other

studies on BPA that were less amenable to the construction of dose-response

relationships but that were otherwise scientifically sound, inclusive of more

advanced and sensitive endpoints, and that were often indicative of BPA impacts

that could potentially portend significant risks to health at lower levels of

exposure than observed in the Tyl studies. Thus, this Subcommittee finds that

these other studies deserve more consideration (and discussion) in the

assessment, despite the fact that these other studies may not be as amenable to

quantitative analysis of dose response. Specifically, the effect of including

additional studies now relegated to the Appendices and the studies mentioned

above is that in the hazard identification phase of risk assessment, additional

endpoints are identified (e.g., prostate, neurobehavioral, mammary) and, in the

dose-response evaluation phase, health effects are identified at levels

substantially lower (at least an order of magnitude lower) than the 5 mg/kg

bw/day NOAEL identified in the Tyl et al studies[3,4]. This makes these studies highly relevant to this

assessment. (Discussed again below). 4. IS THE NO OBSERVED ADVERSE EFFECT

LEVEL (NOAEL) USED IN THIS ASSESSMENT THE APPROPRIATE POINT OF DEPARTURE FOR

CALCULATING THE MARGINS OF SAFETY (MOS), FOR PURPOSES OF THIS SAFETY ASSESSMENT

OR DO DATA SUPPORT THE USE OF AN ALTERNATIVE ENDPOINT? IN SELECTING THE NOAEL,

DID FDA MAKE THE BEST SCIENTIFIC CHOICE BASED ON THE AVAILABLE DATA AND

INFORMATION? The Subcommittee finds that the draft risk assessment

did not sufficiently consider alternative studies in the identification of the

point of departure for calculating the margins of safety. Many studies were

excluded from the quantitative risk assessment due to a variety of specific,

individual deficiencies. However, the large number of positive findings in the

areas of neurobehavioral development, prostate gland, mammary gland and puberty

in females, as identified in the NTP Brief, raises the possibility that BPA

interacts importantly with gonadal hormone receptors during development, and

that these interactions may induce adverse effects in offspring of exposed

mothers at levels at least an order of magnitude below the 5 mg/kg bw/day NOAEL

identified in the draft assessment. Using applied dose (in the absence of

internal dose) the effects of these interactions can be systematized and

quantified into coherent dose-effect relationships (e.g., the data could be

portrayed on a simple diagram showing how various effect measures compare

quantitatively), and they point to a lower NOAEL or a LOAEL. EPA has developed ways to use internal dose to

conduct meta-analysis for organic solvents[10,11].

The approach requires knowledge of the dose metric (e.g., concentration of the

proximal toxicant in the target organ), a viable physiologically-based

pharmacokinetic (PBPK) model for estimating that dose from a variety of

exposure scenarios, and ways to convert effects on a variety of endpoints to a

common scale (‘Effect magnitude’ in the study terminology). This

may be applicable to BPA, given what is known about its binding to ERs, the

organs of concern, the amount of information about the kinetics of BPA already

available, and the wealth of effects that have been reported, and may provide

more confidence in identification of a point of departure. Further, the draft assessment did not attempt to

model the applied dose-response relationships found in the Tyl studies nor any

other study using the readily available Benchmark Dose (BMD) software (www.epa.gov/NCEA/BMDS/).

The advantage of BMD modeling is that confidence intervals on dose (e.g.,

BMDL10) are used as the point of departure, better representing the power of

various studies and providing a consistent basis as point of departure. The Tyl

data, and data from other studies, likely are sufficient and available to

support BMD modeling, and this approach is preferred to the NOAEL/LOAEL

approach. The Subcommittee finds that the

weight-of-the-evidence provides scientific support for including studies by

CERHR as “adequate†in the identification of a point of departure

(as described above). Though these studies individually have limitations, taken

together they provide sufficient support for a point of departure evaluation at

levels of exposure at least an order of magnitude lower than the 5 mg/kg bw/day

level selected by FDA. Notwithstanding concerns expressed above, taking the BPA

exposure assessment in the FDA draft assessment at face value, in which 0-2

month old infants are estimated to have BPA exposure at the 2.3-2.4 μg/kg

bw/day level, the identification of a point of departure at least an order of

magnitude lower than the 5 mg/kg bw/day NOAEL selected by FDA suggests that the

margins of safety from food contact applications are minimal. 5. WERE SCIENTIFIC ASSUMPTIONS THAT

ARE NOT STRICTLY LINKED TO THE DATA EXPLAINED AND APPROPRIATE FOR THE PURPOSES

OF THIS SAFETY ASSESSMENT? As noted elsewhere in this Subcommittee’s

report, the draft assessment does not include a discussion of cumulative

exposures and risk, and the biomonitoring data were not evaluated; hence these

topics were not well explored in the assessment. The human health risks of the

food contact applications may be understated when only a single source of

exposure is considered and limited data are available regarding other food

contact exposures (e.g., PC sippy cups, PC sport bottles). Assumptions of no

biological activity of bisphenol A glucuronide appear to be reasonable based on

data for other glucuronide metabolites. However, the basis for assuming other

metabolites are of no effect is unclear. Moreover, evidence presented in the

NTP brief suggests that even though fetal and neonatal rats have the ability to

metabolize bisphenol A, their metabolic pathways are less efficient than those

of adult rats. However, infants’ and neonates’ ability to

metabolize bisphenol A are not explained in the FDA assessment, although the

rat studies referred to in the NTP brief suggest higher risks for neonates than

is assumed in the draft assessment. 6. ARE THE SCENARIOS ADDRESSED

REPRESENTATIVE, COMPREHENSIVE, AND SCIENTIFICALLY SOUND, CONSIDERING THE PUBLIC

HEALTH RISK EVALUATED? The Subcommittee assumed that this question refers to

exposure scenarios. At the

September 16 meeting, the invited Panel suggested stratifying exposure to BPA

through milk ingestion and defining exposure not as a mean value but at a

number of levels. This approach would be particularly useful if ingestion could

be related to the number of children exposed at each ingestion level, to

improve estimates of exposure on a population basis. Given the limited number

and limited geographic dispersion of the FDA samples analyzed, it is difficult

to assess the representativeness of the samples. [Data are lacking to assess

the representativeness of the scenarios employed in the assessment.] An important problem is the marked

paucity of data on internal exposure of any kind in the most vulnerable

population, especially as some of these infants might have additional exposure

from devices if in an ICU setting. This again speaks to the need to consider

cumulative exposures and differential risk in neonates. 7. ARE THE RECOMMENDED STUDIES IN

THE TIERED TESTING STRATEGY PRESENTED APPROPRIATE IN RELATION TO BISPHENOL A EXPOSURE

THROUGH THE USE OF FOOD CONTACT APPLICATIONS, AND WILL THOSE STUDIES REDUCE THE

UNCERTAINTIES ASSOCIATED WITH THE ASSESSMENT? PLEASE SUGGEST ANY OTHER

RECOMMENDED STUDIES AND/OR ENDPOINTS THAT YOU THINK WOULD BE USEFUL FOR FUTURE

ASSESSMENTS. Pharmacokinetic studies will be essential

for integrating findings from the many studies that used non-oral routes of

exposure. Emphasis should be placed on developing PBPK models for model species

and humans, so that comparisons of dose can be made across species in a

rational, quantitative manner. In addition, methods to quantitatively compare

disparate endpoints should be explored, so that effects in different systems

can be placed on common axes (see response to question 4, above). These

approaches may enable quantitative synthesis of dose-effect functions across

endpoints that currently are not comparable. The biomonitoring recommended by FDA in the draft

assessment (both in humans and in experimental animals) will be very useful for

improving estimates of exposure, which is a weakness of the current assessment.

Studies in non-human primates would be valuable, but

should be limited due to expense and ethical concerns. Well-parameterized PBPK

models can address the issues of species-specific metabolism of BPA, and should

enable accurate extrapolation from rodents to humans. Uncertainty related to

species-specific endocrine-dependent development will be reduced through

research in primates. Rodent studies could be performed to seek

plausibility for the JAMA study[5].

Does BPA exposure actually influence insulin resistance in vivo and is this

influenced by deletion of the adiponectin receptor? Does BPA exposure elevate

blood pressure or enhance the response to thrombogenic stimuli in vivo in a

dose dependent manner and how does this relate to urinary (“totalâ€)

BPA? Does BPA exposure accelerate atherogenesis in predisposed mice in a dose

dependent manner? Are any of these effects influenced by gender? The areas of

research identified above, i.e., biomonitoring studies, PBPK models, rodent and

non-human primate studies will provide a large amount of useful information.

However, except for classification into “tiers†there is no

priority assigned to the tasks. From a public health perspective one might

select first to identify areas that are most likely to contradict the

conclusion of the draft FDA report to take no regulatory action. In addition to the recommendations in the assessment,

a large rodent study should be considered to address the central question of

the developmental toxicity of BPA. To this end, the study must be designed (1)

to meet criteria for acceptance established by the FDA or reasonable criteria

applied by the scientific community for study evaluation that FDA should adopt,

(2) to address the endocrine mechanism-based concerns of the scientific

community, and (3) to use endpoints and models validated for the study of

endocrine-mediated developmental processes. Appropriate endpoints have been

developed to address questions of development of structure and function of the

nervous system (and other endpoints of concern), and experimental designs and

statistical analyses exist that can optimize the study for purposes of risk

assessment[12]. Finally, akin to

the case with the pharmaceutical industry, any data generated subsequent to the

initial approval of a product should be released to the FDA in a timely fashion

for review by an independent body. 8. DO THE ASSESSMENT RESULTS OBJECTIVELY

AND TRANSPARENTLY SUPPORT THE CONCLUSIONS? ARE THEY SUPPORTED BY THE AVAILABLE

DATA AND SCIENCE? The Subcommittee finds that the draft assessment

conclusions are not supported by the available data and science unless the

arguments for excluding all work on effects of BPA except the Tyl studies are

accepted. While these may be the only available studies designed to address

questions immediately pertinent to regulatory science, the studies excluded

from the quantitative analysis raise additional and unsettling concern about

potential effects from exposure to BPA, as indicated by the NTP Brief and the

comments from the invited Panel that were received by the Subcommittee. For

example, the new evidence on associations of urinary BPA with disease[5] and on estrogen-mediated synaptogenesis[6,7], limited as they are, indicate the

need for further consideration of the potential toxicity of BPA in adults. In regard to the exposure data, the report would be

strengthened if the selection of the data used to estimate exposure were better

justified, data variability were more appropriately summarized and information

on the distribution of exposure values (rather than average value) were

considered in the assessment. Consistent and credible criteria for study inclusion,

recommended by the Subcommittee, would be to use those studies that are judged

as “adequate†by CERHR in the FDA hazard, dose-response and safety

assessment of BPA. In addition, several studies of effects of BPA on adult

humans and animal species that were published after the draft assessment was

finished should be considered for inclusion in the final assessment. Combining

qualitative and quantitative information from the CERHR-identified studies with

the draft FDA exposure assessment (which may or may not be

“conservativeâ€), provides a basis for the Subcommittee to

reasonably conclude that the Margins of Safety are far less than those defined

by FDA as “adequateâ€. 9. DO YOU HAVE ANY ADDITIONAL COMMENTS THAT WOULD ASSIST

FDA IN REFINING THE ASSESSMENT? The approach of requiring

guideline-worthy studies (e.g., large N, GLP protocols) perforce eliminates a

great deal of relevant information from consideration in the risk assessment, and

begs the question of the utility of data collected for academic and other

purposes. Development of meta-analytical methods for systematizing these

disparate data sets would facilitate their use in quantitative risk assessments

in general or, in the absence of a meta-analysis, a more comprehensive

weight-of-the-evidence evaluation. In particular, a limited sensitivity

analysis summarizing the impact of inclusion of appropriately selected

alternative studies on the conclusions of the report would be useful. 10. DOES THE

INFORMATION AND DATA IN APPENDICES 1 AND 2 SUPPORT THE UNDERLYING ASSUMPTIONS

USED IN THE INTERIM ASSESSMENT? The information and data in Appendices 1 and 2

provide the limitations of individual studies and discuss the FDA’s

rationale for excluding each of them from the formal risk assessment. This

approach creates a false sense of security about the information that is used in the assessment, however, as it

overlooks a wide range of potentially-serious findings. It is not clear that

the information in the Appendices supports the assumptions discussed in the

draft assessment. SUMMARY The Subcommittee appreciates the clarity of the draft

safety assessment of bisphenol A in food contact applications. The literature

review was thorough and the criteria for reliance on the Tyl studies in the

generation of a quantitative risk/safety assessment were made amply clear. The

strengths of the draft safety assessment notwithstanding, the Subcommittee

identified several significant concerns with the assessment in its current

form. The exposure assessment lacks an adequate number of infant formula

samples and relies on mean values rather than accounting for the variability in

samples. The draft lacks a clear description of the criteria for eliminating an

increasing number of non-GLP studies that indicate the possibility of toxic

effects that are not mediated by interaction of BPA with the estrogen receptor,

and the Subcommittee does not agree with the exclusion of the non-GLP studies

in the safety assessment. Additional concern is expressed with the calculation

of the NOAEL and specifically whether the exposure assessment to ‘at

risk’ infants with minimal or impaired metabolic function and exposures

from medical devices and procedures is as conservative as the assessment

claims. In fact, it is the judgment of the Subcommittee that lack of

consideration of the totality of exposures from other sources severely limits

the usefulness of the safety assessment with respect to food contact

applications. The final assessment should also include evaluation of a number

of studies that appeared after the completion of the current draft or were

otherwise identified by the Subcommittee. The Subcommittee identified a need for

application of state-of-the-art risk assessment methods in this assessment,

which will enable utilizing all appropriate scientific information available on

the potential toxicity of BPA. For example, methods developed at the EPA could

expand the range of data sources used in the assessment to include academic and

government-sponsored studies that are not necessarily GLP-compliant. This

approach would be consistent with the opinions of the NTP regarding studies

that it judged to be adequate and having utility for the BPA safety assessment.

Finally, research is needed to develop and improve methods for quantitative

evaluation of existing data to incorporate mechanistic studies into the risk

assessment of BPA and other chemicals. ACKNOWLEDGEMENTS The Subcommittee gratefully acknowledges the

administrative support provided by Pena, Ph.D., and the input of the

invited Panel and other participants in the September 16, 2008 public meeting. LITERATURE CITED 1. Timms, B.G., Howdeshell, K.L., Barton,

L., Bradley, S., Richter, C.A., and vom Saal, F.S. (2005) Estrogenic chemicals

in plastic and oral contraceptives disrupt development of the fetal mouse

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National Academy of

Sciences (

USA ) 102(19):7014-7019. 2. Ho, S.M., Tang, W.Y., Belmonte de Frausto, J.,

Prins, G.S. (2006) Developmental exposure to estradiol and bisphenol A

increases susceptibility to prostate carcinogenesis and epigenetically

regulates phosphodiesterase type 4 variant 4. Cancer

Research 66(11):5624-5632. 3. Tyl, R.W., Myers, C.B., Marr, M.C., Sloan, C.S.,

Castillo, N.P., Veselica, M.M., Seely, J.C., Dimond, S.S., Van , J.P.,

Shiotsuka, R.N., Beyer, D., Hentges, S.G., Waechter, J.M.,Jr. (2008)

Two-generation reproductive toxicity study of dietary bisphenol A (BPA) in CD-1

(Swiss) mice. Toxicological Sciences 104(2):

362-384. 4. Tyl, R.W., Myers, C.B., Marr, M.C., , B.F.,

Keimowitz, A.R., Brine, D.R., Vesilica, M.M., Fail, P.A., Chang, T.Y., Seely,

J.C., Butala, J.H., Dimond, S.S., Cagen, S.Z., Shiotsuka, R.N., Stropp, G.D.,

Waechter, J.M. (2002) Three-generation reproductive toxicity study of dietary

bisphenol A in CD Sprague-Dawley rats. Toxicological

Sciences 68(1): 121-146. 5. Lang, I.A., Galloway, T.S., Scarlett, A.,

Henley , W.E., Depledge, M., Wallace,R.B., and Melzer, D.

(2008) Association of urinary bisphenol A concentration with medical disorders

and laboratory abnormalities in adults. Journal

of the American Medical Association 300(11):1303-1310. 6. Leranth, C., Hajszan, T., Szigeti-Buck, K., Bober,

J., and Macy, N.J. (2008) Bisphenol A prevents the synaptogenic response to

estradiol in hippocampus and prefrontal cortex of ovariectomized nonhuman

primates. Proceedings of the National

Academy of Sciences ( USA )

105(37):14187-14191. 7. Leranth, C., Szigeti-Buck, K.,

Macy , N.J. ,

and Hajszan, T. (2008) Bisphenol A prevents the synaptogenic response to

testosterone in the brain of adult male rats. Endocrinology

149:988-994. 8. Dolinoy ,

D.C. , Huang, D., and Jirlte, R.L.

(2007) Maternal nutrient supplementation counteracts bisphenol A-induced DNA

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9. Fein, S.B., and Falci, C.D. (1999)

Infant formula preparation, handling, and related practices in the

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(2005) Toward cost-benefit analysis of acute behavioral effects of toluene in

humans. Risk Analysis 25:447-456.

11. Benignus, V.A., Boyes, W.K., Kenyon, E.M., and

Bushnell, P.J. (2007) Quantitative comparisons of the acute neurotoxicity of

toluene in rats and humans Toxicological

Sciences 100:146-155. 12. Li, A.A., Baum, M.J., McIntosh, L.J., Day, M.,

Liu, F., Gray, L.E. Jr., (2008) Building a scientific framework for studying

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nervous system. NeuroToxicology 29(3):504-519.

ABBREVIATIONS BMD Benchmark Dose BMDL10 95% lower confidence limit on the Benchmark

Dose at the 10% response level BPA Bisphenol A CERHR

Center for the Evaluation

of Risks to Human Reproduction EFSA European Food Safety Authority EPA U.S. Environmental Protection Agency EU RAR European Union Risk Assessment Report FDA Food and Drug Administration GLP Good Laboratory Practice HOMA Homeostasis Model Assessment ICU Intensive Care Unit JAMA Journal of the American Medical Association LOAEL Lowest Observed Adverse Effect Level MOS Margin of Safety NHANES National Health and Nutrition Examination

Survey NIH National Institutes of Health NIEHS National Institute of Environmental Health

Sciences NOAEL No Observed Adverse Effect Level NTP National Toxicology Program PBPK Physiologically-Based Pharmacokinetic PC Polycarbonate UF Uncertainty Factor USFDA

United States Food and Drug

Administration APPENDIX

1: PUBLIC MEETING NOTICE

DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2008–N–0038] Bisphenol A Subcommittee of the Science Board to the Food

and Drug Administration; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION: Notice. This notice announces the following meeting:

Bisphenol A (BPA) Subcommittee of the Science Board to the Food and Drug

Administration (FDA) meeting. The topic to be discussed is the draft

assessment of BPA for use in food contact applications. The Subcommittee will

hear and discuss the draft assessment of BPA for use in food contact

applications, including oral presentations from the public. Date and Time: The meeting will be held

on September 16, 2008, at 9 a.m. to 3:30 p.m. Location: Hilton Washington, WashingtonDC/Rockville

Executive Meeting Center, Plaza Ballroom, 1750 Rockville Pike, Rockville, MD

20852. Contact Person:

Pen˜ a, Office of Science and Health Coordination, Office of the

Commissioner (HF–33), Food and Drug Administration, 5600 Fishers Lane,

(for express delivery, rm. 14B–08) Rockville, MD 20857,

301–827–3340, or by e-mail: .Pena@...

or FDA Advisory Committee Information Line,

1–800–741–8138 (301–443–0572 in the Washington,

DC area), code 3014512603. Please call the Information Line for up-to-date

information on this meeting. A notice in the Federal Register about last minute modifications that impact

a previously announced advisory committee meeting cannot always be published

quickly enough to provide timely notice. Therefore, you should always check

the agency’s Web site and call the appropriate advisory committee hot

line/phone line to learn about possible modifications before coming to the

meeting. Agenda: The

Subcommittee will hear and discuss the draft assessment of BPA for use in

food contact applications, including oral presentations from the public.

FDA’s draft assessment of BPA and FDA’s charge to the

Subcommittee will be posted on or after August 15, 2008, on FDA’s Web

site at http://

www.fda.gov/ohrms/dockets/ac/ acmenu.htm, click on the year 2008

and scroll down to the appropriate advisory committee link. FDA intends to

make background material available to the public no later than 2 business

days before the meeting.

If

FDA is unable to post the background material on its Web site prior to the

meeting, the background material will be made publicly available at the

location of the advisory committee meeting, and the background material will

be posted on FDA’s Web site after the meeting. Background material is

available at http://www.fda.gov/ohrms/

dockets/ac/acmenu.htm, click on the year 2008 and scroll down to

the appropriate advisory committee link. Procedure:

Interested persons may present data, information, or views, orally or in

writing, on issues pending before the Subcommittee. Written submissions may

be made to the contact person on or before September 12, 2008. Oral

presentations from the public will be scheduled between approximately 11 a.m.

and 12 noon and between approximately 1 p.m. and 2 p.m. on September 16,

2008. Those desiring to make formal oral presentations should notify the

contact person and submit a brief statement of the general nature of the

evidence or arguments they wish to present, the names and addresses of

proposed participants, and an indication of the approximate time requested to

make their presentation on or before September 4, 2008. Time allotted for

each presentation may be limited. If the number of registrants requesting to

speak is greater than can be reasonably accommodated during the scheduled

open public hearing session, FDA may conduct a lottery to determine the speakers

for the scheduled open public hearing session. The contact person will notify

interested persons regarding their request to speak by September 5, 2008.

Persons attending FDA’s advisory committee meetings are advised that

the agency is not responsible for providing access to electrical outlets. FDA

welcomes the attendance of the public at its advisory committee meetings and

will make every effort to accommodate persons with physical disabilities or

special needs. If you require special accommodations due to a disability,

please contact Dr. Pen˜ a at least 7 days in advance of the

meeting. FDA is committed to the orderly conduct of its advisory committee

meetings. Please visit our Web site at http://www.fda.gov/oc/advisory/

default.htm for procedures on public conduct during advisory

committee meetings. Notice of this meeting is given under the Federal

Advisory Committee Act (5 U.S.C. app. 2). Dated: August 11, 2008. Shuren, Associate Commissioner for Policy and Planning. [FR

Doc. E8–18864

APPENDIX 2: INVITED PANEL ROSTER LESLIE BENET, PHD UNIVERSITY OF

CALIFORNIA 533 PARNESSUS, ROOM U-68 SAN

FRANCISCO, CA 94143-0912 L. EARL GRAY, JR., PHD SENIOR

REPRODUCTIVE BIOLOGIST AND TOXICOLOGIST REPRODUCTIVE TOXICOLOGY DIVISION OFFICE OF RESEARCH AND DEVELOPMENT NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH

LABORATORY U.S.

ENVIRONMENTAL PROTECTION AGENCY RESEARCH

TRIANGLE PARK, NC 27711 STEVEN HENTGES, PHD AMERICAN PLASTICS COUNCIL 1300

WILSON BOULEVARD SUITE 800 ARLINGTON,

VA 22209 SONYA LUNDER SENIOR ANALYST ENVIRONMENTAL WORKING GROUP 1436 U ST, SUITE 100 NW WASHINGTON DC 20009 D. GAIL MCCARVER, MD CO-DIRECTOR,

DEPARTMENT OF PEDIATRICS BIRTH DEFECTS RESEARCH CENTER MEDICAL COLLEGE OF

WISCONSIN 8701 WATERTOWN PLANK RD. MILWAUKEE, WI 53226 KRISTINA A. THAYER, PHD NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES NATIONAL INSTITUTES OF HEALTH RESEARCH

TRIANGLE PARK, NC 27709 FREDERICK S. VOM SAAL, PHD UNIVERSITY OF MISSOURI-COLUMBIA DIVISION OF BIOLOGICAL SCIENCES 105 LEFEVRE HALL COLUMBIA,

MO 65211