Procedural Review of Health Reference Values Established by enHealth for PFAS

Prepared by

Prof (Adj) Andrew Bartholomaeus

School of Pharmacy

Faculty of Health

University of Canberra

Therapeutic Research Centre

School of Medicine

University of Queensland

30 August 2016

Contents

1Terms of Reference

2Background – The enHealth Process

3Comments on Administrative Aspects of the enHealth Process

4EFSA and US EPA Assessments

4.1Preliminary Observations

4.1.1What are HRVs

4.1.2Balancing Risk

4.1.3Status of Current Human Health Reference Values (HRVs)

4.1.4The Basic Process for Conducting HHRAs

4.1.5Basic Issues in Assessment of Epidemiology Studies

5Sources of variation between enHealth Workshop, EFSA and US EPA Risk Assessments

5.1Toxicology and Selection of the PoD

5.1.1PFOS

5.1.2PFOA

5.2Toxicokinetics

5.3Mechanisms of Action

5.3.1Pharmacokinetics

5.3.2Toxicity

5.3.3Comment

5.4Epidemiology

5.4.1Exposure

5.4.2Carcinogenicity

5.4.3Reproductive effects

5.4.4Other Effects

6Conclusions

6.1Use of International Risk Assessments and derived HRVs

6.2Sources of Differences Between US EPA and EFSA Risk Assessments

6.3Potential Public Health Consequences of the Choice of HRVs

6.4Balancing Risk Mitigation with Risk Generation

6.5Overall Conclusion

7Recommendations

8References

1Terms of Reference

In early August 2016 the Department of Health commissioned this review in fulfilment of the Government’s commitment to review the interim human health reference values (HRVs) for per- and poly-fluorinated alkyl substances (PFAS) in drinking water. Delivery of the review was therefore considered urgent and a period of one month was allocated.

The Terms of Reference endorsed by the Government for this independent review are as follows:

“The independent review will consider:

(1)Approaches and assumptions used by the European Food Safety Authority (EFSA), as outlined in the reports Perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA) and their salts, Scientific Opinion of thePanel on Contaminants in the Food Chain (EFSA, 2008) and Perfluoroalkylated substances in food:occurrence and dietary exposure (EFSA, 2012).

(2)Approaches and assumptions used by the United States Environmental Protection Agency(US EPA), as outlined in the 2016 Health Effects Support Document for PerfluorooctaneSulfonate (PFOS) (US EPA, 2016b) and the 2016 Health Effects Support Document for Perfluorooctanoic Acid(PFOA)(US EPA, 2016a).

(3)The applicability and relevance of these approaches and assumptions in the Australiancontext, having regard to existing Australian regulatory science policy as described in suchguidance materials as:

  1. Australian Pesticide and Veterinary Medicines Authority (APVMA) Data guidelines( and Application ofscience to regulatory risk assessment (
  2. the enHealth Environmental Health Risk Assessment, Guidelines for Assessing HumanHealth Risks from Environmental Hazards (enHealth, 2012);
  3. the Food Standards Australia New Zealand (FSANZ) Risk Analysis in Food Regulation publication:( regulation/Pages/de fault.aspx(FSANZ)
  4. the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) Handbook for notifiers:
  5. the National Health and Medical Research (NHMRC) Guidelines for Managing Risks inRecreational Water (NHMRC, 2008)and NHMRC Australian Drinking Water Guidelines (NHMRC, 2016).

Given the limited time available, and the considerable body of documentation, the primary focus of this review is to identify the principle sources of variation between the US EPA and EFSA risk assessments of PFAS and the resultant guidance values, to comment on the consistency of the approaches taken with Australian guidance on, and practice of, health risk assessment and to form a view on the suitability of the EFSA values selected by enHealth as an interim measure pending more extensive consideration by FSANZ. In the time available for this review it is not possible to definitively identify one or other of the approaches as “correct” and the other not. Rather, the potential sources of strength and weakness in each assessment are examined together with a consideration of the nature and significance of methodological deviations from general regulatory approaches.

2Background – The enHealth Process

The Standing Committee on Environmental Health (enHealth) under the guidance of the Australian Health Protection Principle Committee (AHPPC) provides nationally agreed environmental health policy advice, based on the best available evidence and expertise, to the Australian Health Ministers Advisory Council (AHMAC) through the AHPPC. The committee consists of representatives from key Commonwealth departments, each of the States and Territories, and New Zealand. In addressing specific public health issues enHealth draws on specialist scientific and medical expertise through the establishment of working groups and or the programming of workshops where the issue can be discussed in detail, applying a multidisciplinary approach. Unlike Australian regulators of chemicals in food, FSANZ and APVMA, and international agencies such as the US EPA, US FDA or EFSA, enHealth is not supported by a specialist scientific secretariat (that is a risk assessment group) and therefore relies on members of its scientific workshops and the agencies of the enHealth membership to prepare background papers for consideration by the medical and scientific experts of its scientific workshops.

On 15 March 2016, the AHPPC endorsed the enHealth Guidance Statements on Perfluorinated Chemicals (PFCs), which include an undertaking by enHealth to convene an expert group, in early 2016, to provide advice to the AHPPC on the development of an Australian interimHRV for perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) for consistent use in the undertaking of human health risk assessments and the management of contaminated sites across Australia. In developing the interim HRV, the workshop was to consider relevant international guidelines, as well as contemporary scientific and technical issues. This workshop was convened in April 2016 and provided recommendations for the establishment of HRVs to support jurisdictional responses to incidents of environmental contamination with PFAS and to set drinking water guideline values for these substances. The enHealth committee was aware that a number of international regulatory bodies and the OECD had previously considered the HRVs for PFAS based on access to a larger data base of published and unpublished studies than was readily available in Australia at short notice. EnHealth was also aware that there was an immediate need for HRVs to be identified for use by State and Territory environment agencies in the management of PFAS contamination of ground water and of food produced in contaminated areas. EnHealth therefore undertook to review overseas Human Health Risk Assessments (HHRA) and standards rather than a de novo assessment, and based on a consideration of these,determinetemporary/interim Australian HRVs and drinking water guideline values for PFOS,PFOA and related substances. This view was reinforced by the knowledge that the US EPA values were then in draft, that it was understood that EFSA intended that their values would be underreview, and that a more detailed review of HRVs for PFAS was due to commence in FSANZ.

The workshops comprised of recognised experts from a range of scientific disciplines of direct relevance to the objectives of the workshop and involved a consideration of international assessments with a principle focus on those of EFSA and the US EPA. Attendees included toxicologists, members of the enHealth committee, representatives of the CooperativeResearch Centre for Contamination Assessment and Remediation of the Environment(CRC CARE), FSANZ,the Australian GovernmentDepartment of Health and Australian Government Department of the Environment. Scientific and medical experts on the workshop were tasked with preparing and presenting papers on the toxicology and health effects of PFAS, and the differences in approach of the US EPA and EFSA for discussion, reflecting their respective expertise.

The international PFOS and PFOA HRV reviews considered by the workshop included;

(1)European Food Safety Authority(EFSA, 2008);

(2)United States Environmental Protection Agency (USEPA);

  1. Health Effects Support Document for PFOS 2014 (draft)(US EPA, 2014a);
  2. Health Effects Support Document for PFOA 2014 (draft)(US EPA, 2014b);
  3. Provisional Health Advisories for PFOA and PFOS 2009 (US EPA, 2009b);
  4. Soil screening levels for PFOA and PFOS 2009(US EPA , 2009a);

(3)United States Agency for Toxic Substances and Disease Registry (ATSDR, 2015) (draft);

(4)Danish Ministry of the Environment (Perfluoralkylated substances: PFOA, PFOS and PFOSA: Evaluation of health hazards and proposal of a health based quality criterion for drinking water, soil and groundwater., 2015);

(5)German Ministry of Health Drinking Water Commission and Federal EnvironmentAgency, 2006 (GDWC, 2006);

(6)Swedish Environmental Protection Agency, 2012 and 2014 (cited in Danish Ministry ofthe Environment document);

(7)United Kingdom Committee on Toxicity of Chemicals in Food (COT) (COT, 2006a; COT, 2006b; COT, 2009; COT, 2014);

(8)Minnesota Department of Health (MDH, 2009a; MDH, 2009b); and

(9)CRC CARE 2016 (draft).

During consideration of the available reviews and established HRVs (Table 1), and the approach and assumptions utilised by the various regulatory agencies,the workshop engaged in extensive discussion of the relative merits and weaknesses of those assessments. Individual experts of the workshop identified potential strengths and deficiencies in both the assessment by EFSA and that of the US EPA. Although the workshop identified a number of issues impinging on the establishment of appropriate HRVs and discussed specific recommendations for these values there was not a final consensus on the treatment of uncertainties and the relative merits or otherwise of the approaches of EFSA and the US EPA.

The time and resources available to the workshop to explore these issues was necessarily limited, and enHealth were aware of the pending thorough review of PFAS HRVs by FSANZ. In this context the workshop noted that;

  • Because of the exceptionally long half-life (time required for blood levels to decrease by half once dosing has ceased) of PFAS in humans the systemic (i.e. internal) exposure to PFAS is determined by oral (or other routes of) exposure over long periods of time. As lowering of HRVs and drinking water guideline values cannot therefore affect internal exposures meaningfully over the short to medium term, and given the steps already taken to reduce exposure in affected communities, lowering the HRVs established by EFSA would have no short term impact on public health.
  • The establishment of interim HRVs substantially lower than those of EFSA had the potential to greatly constrain the FSANZ review.
  • The EFSA HRVs were therefore concluded to be adequately protective for short to medium term exposures as a temporary measure.
  • The FSANZ review would have greater scope in terms of time and resources than the enHealth workshop and could draw on the deliberations of the workshop to inform that review.

The enHealth committee therefore determined to utilise the EFSA HRVs as temporary (i.e. interim) values pending the finalisation of the FSANZ review.

The enHealth committee, meeting on 6 April 2016, considered the outcome of the technical workshop from the day before and agreed to have a workshop report prepared and, based on a consideration of this, to make recommendations to AHPPC. On the 26th of May 2016 enHealth met again by teleconference to consider a draft workshop report and consider their next steps. The record of outcomes states:

“Members noted the draft Workshop report prepared by [one of the invited experts] and that comments and suggested edits were in the process of being incorporated.

“Members noted that the workshop report may take longer than was desirable to finalise, and so agreed that enHealth proceed instead with a short statement on recommended interim human health reference values (the “enHealth statement”). A first draft of the statement was provided by SA Health. The draft set out, as a summary, many of the issues discussed at the workshop.”

EnHealth made the following decisions;

1)Adoption of Tolerable Daily Intake (TDI) values derived by the European Food Safety Authority (2008).

Members agreed that the EFSA approach is acceptable. Members further agreed that the US EPA health advisories on perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), released in May 2016, should be considered and a response included in the statement.

2)Adoption of the same TDI value proposed for PFOS for perfluorohexane sulfonate (PFHxS).

Given the comparative toxicity, members agreed that the PFOS TDI value be adopted also for PFHxS. The practical effect of this is that in applying the TDI for PFOS, any PFHxS present will also need to be taken into account.

3)Adoption of interim drinking water guideline values for PFOS and PFOA.

Members agreed to adopt interim drinking water guideline values based on the EFSA TDIs and application of the methodology used in the Australian Drinking Water Guidelines (ADWG). These would be used for site-specific assessments. Members discussed the desirability of the NHMRC undertaking a formal process for establishing guideline values in the ADWG and agreed that this should be considered further following the completion of the work FSANZ is undertaking to establish health based guidance values for promulgation in the Australia New Zealand Food Standards Code.

4)Adoption of interim guideline values for surface water (recreational water and fish consumption).

Members agreed to adopt interim water quality guideline values for recreational water based on the approach recommended by the NHMRC, effectively 10 times the value of the drinking water guideline values.

Members agreed that the assessment of any health risks from contaminated seafood would be based on the levels detected in the seafood. As such, there was no requirement to set a level in water from which seafood is taken.

5)Adoption of seafood screening guideline values.

Members agreed that the interim TDIs would form the basis of site –specific risk assessments. As such, general seafood screening guideline values were not required.

6)Updating the enHealth Guidance Statements and Factsheet.

Members agreed that the Guidance Statements and Factsheet would be updated to include: (i) a reference to the enHealth statement on interim TDIs and water quality guideline values; and (ii) information about PFHxS.

Members also agreed to develop a “Questions and Answers” guide to facilitate consistent responses by jurisdictions to media enquiries about the interim reference values and the inclusion of PFHxS.

7)Changing references from “perfluorinated chemicals (PFCs)” to “per- and poly-fluoroalkyl substances (PFAS)”.

Members agreed to adopt the change in nomenclature for this group of chemicals.

8)Seek AHPPC endorsement of the enHealth statement on interim TDIs and updated Guidance Statements and Factsheet.

Members discussed the next steps and agreed that the enHealth statement and updated Guidance Statements and Factsheet should be provided to the AHPPC for consideration and endorsement.

A finalised record of the outcomes of the workshop was not available at the time of this review, however an uncirculated draft outcomes document was provided. The draft record of outcomes indicates that the workshop gave detailed consideration to the principal studies, points of departure, toxicological endpoints and uncertainty factors used to derive the HRVs of the different agencies considered. As many agencies had based their own reviews on that of EFSA, ATSDR or US EPA the workshop gave most attention to these. The workshop also carefully considered the different modelling approaches used by the US EPA and EFSA, as discussed later in this report.

As the EFSA and USEPA HRVs represent the upper and lower bounds of the HRVs considered by enHealth the focus of this review (and the terms of reference) is a comparison of those assessments and the enHealth deliberations on them. The US EPA has subsequently finalised its assessment of PFAS and the resultant HRVs. The terms of reference for this review directs attention to the finalised US EPA reviews of 2016. Consequently, this review considers the finalised US EPA review in place of the Draft available to enHealth at the time it completed its considerations.

Subsequent to the completion of the enHealth consideration, FSANZ has commenced a separate review of PFAS HRVs and will consider whether Maximum Levels (i.e. permissible levels) or some other guidance, should be set for PFAS in food. Additional information available subsequent to the enHealth assessment, the outcomes of the enHealth workshop, and the recommendations of this review will be available for consideration in the FSANZ review. FSANZ will also have the discretion to utilise experts in specific aspects of the PFAS as required.

Table 1 Health Reference Values for PFOS and PFOA from International Regulatory Agencies

PFOS / PFOA
PoD
mg/kg/d / UF / TDI/RfD
ng/kg/d / PoD
mg/kg/d / UF / TDI/RfD
ng/kg/d
EFSA 2008 / 0.03 / 200 / 150 / 0.3 / 200 / 1500
USEPA 2016 / 0.00051# / 30 / 20 / 0.0045# / 300 / 20
ATSDR 2015 / 0.00252# / 90 / 30 / 0.00154# / 90 / 20
Danish EPA 2015 / 0.033 / 1230 / 30 / 0.003# / 30 / 100
USEPA DWG 2009 / 0.03 / 390 / 80 / 0.46 / 2430 / 190
Minnesota 2009 / 0.0025# / 30 / 80 / 0.0023# / 30 / 77
Germany 2006 / 0.025 / 300 / 100 / 0.1 / 1000 / 100

# Based on the human equivalent dose derived from theoretical pharmacokinetic modelling and incorporating a variety of assumptions to compensate for data deficiencies.

3Comments on Administrative Aspects of the enHealth Process

EnHealth provides a highly valuable and appropriate consultative jurisdictional forum to support co-ordinated approaches to environmental health issues across the Commonwealth and New Zealand (NZ). The use by enHealth of expert working groups to provide specialist medical and scientific expertise to support its work is consistent with that of most major international regulatory agencies, including EFSA and the US EPA, with the Australian Therapeutic Goods Administration (TGA), and to a degree, that of FSANZ and the APVMA. Where the enHealth process deviates is that it does not include a dedicated, specialist scientific secretariat (a risk assessment group) to support its work. Most regulators utilise a scientific secretariat to prepare initial risk assessments that address the available data, draw conclusions, make recommendations and pose specific scientific questions for the expert committee to address. The expert committees then address the specific recommendations and questions, critique the overall assessment and provide recommendations for further work. This process ensures that expert committees have all the necessary information at their disposal, and can then focus their individual attention and their available time on the specific aspects of the assessment that their specialist expertise can most add value to. The advantage of this approach is that the decision making process is considerably more transparent, the available expert resources are utilised efficiently, the scientific line of reasoning is documented in detail, approaches to HHRA are consistent, and where appropriate the engagement of external stakeholders is facilitated through public consultation processes such as those of EFSA, US EPA and FSANZ.