December 29, 2014 MEMORANDUM
FROM: Kelly Sherman, Human Studies Ethics Review Officer, Office of the Director Office of Pesticide Programs
TO: Christina Swartz, Chief, Risk Assessment Branch II Health Effects, Division Office of Pesticide Programs
REF: Hansson, T. and Roos, B. (1987). The Effect of Fluoride and Calcium on Spinal Bone Mineral Content: A Controlled, Prospective (3 Year) Study. Sahlgren’s Hospital, University of Gothenberg, Sweden. Calcified Tissue International. 40:315-7. (MRID 49489102)
I have reviewed the referenced human toxicity study with fluoride. I conclude that if the study is determined to be scientifically valid and relevant, there is no regulatory barrier to EPA relying on this research in actions taken under FIFRA or §408 of FFDCA.
Summary Characteristics of the Research
In this study, 100 postmenopausal women were placed into four treatment groups (25 per group) and given fluoride and/or calcium daily over a 3-year period. Group 1 was given 30 mg/day sodium fluoride (13.6 mg fluoride/dose) and 1 g/day calcium, Group 2 was given 10 mg/day sodium fluoride (4.5 mg fluoride/dose) and 1 g/day calcium, Group 3 was given 1 g/day calcium, and Group 4 was given starch as a placebo (capsule). The mean age of the women in the study was 66±6 years. Changes in bone mineral content of the third lumbar vertebra (L3) were measured by dual photon absorptiometry at the start of treatment and then again at 1 year, 1.5 years, 2 years, and 3 years.
1. Value of the Research to Society:
The objective of this study was to investigate the changes in bone mineral content as a result of receiving doses of fluoride and calcium that were lower than those shown to increase bone mass and decrease fractures in earlier studies. The researchers also collected information about adverse reactions or side effects. The study was conducted at Sahlgren’s Hospital, University of Gothenberg, Sweden. The results were published in Calcified Tissue International in 1987. The study was partially funded by grants from the Swedish Medical Research Council and Asker’s Foundation. EPA is proposing to use the study in its assessment of the acute dietary risks of fluoride residues that result from some uses of the fumigant sulfuryl fluoride.
2. Subject Selection:
a. Demographics. One hundred female subjects (mean age 66±6 years) participated in the study.
b. Pregnancy and Nursing Status. The subjects were postmenopausal and therefore not pregnant or nursing.
c. Recruitment. There is no information about how the subjects were recruited, but it is likely that they were patients who had been treated at Sahlgren’s Hospital for vertebral compression fractures.
3. Risks and Benefits:
a. Risks. There is no information about how the potential risks were evaluated nor whether the risks were explained to potential subjects before they agreed to participate. The article notes that the highest dose of fluoride in the study (30 mg fluoride) was equal to the amount of fluoride potentially swallowed by children following prophylactic dental treatment with fluoride gel (30 mg fluoride), so presumably the dose level was considered safe at the time.
b. Benefits. There are no benefits to the subjects.
c. Risk-Benefit Balance. There is no information about the risk-benefit balance. The researchers may have considered the potential societal benefits of increased understanding of fluoride effects to have outweighed the risks associated with the study because the highest dose level of fluoride (30 mg) was likely considered safe because previous studies were conducted with higher doses, although it is noted in the article that the higher doses in the other studies “induce[d] significant side effects.”
4. Independent Ethics Review: There is no information about whether the study underwent independent ethics review.
5. Informed Consent: There is no information about whether the subjects provided informed consent.
6. Respect for Subjects. There is no information about whether subjects were compensated for participating, or whether they were afforded the right to withdraw from the study at any time. The subjects’ identifies are not revealed in the study report.
Applicable Standards Standards
Applicable to the Conduct of the Research
The portions of EPA’s regulations regarding the conduct of research with human subjects, 40 CFR part 26 subpart A – L, do not apply since the research was neither conducted nor supported by EPA, nor was it conducted by a person with the intention to submit the results to EPA.
This research was conducted in Sweden in the early 1980s by physicians in the Department of Orthopedic Surgery (Hansson) and the Department of Radiophysics (Roos) at Sahlgren’s Hospital. In the 1980s in Sweden, independent ethics review of biomedical research would have been prevalent (Solbakk, 1991; Attachment 1). Ethics review committees were first established in Sweden in 1965, and by 1978 the Swedish Medical Research Council proposed mechanisms for formalizing the research ethics committee system in Sweden (Solbakk, 1991). The principles applied by the committees likely would have derived from commonly accepted international principles of research ethics such as those articulated in the Declaration of Helsinki (Solbakk, 1991). Current laws and regulations governing the conduct of human research in Sweden were not in place in the 1980s.
Standards Applicable to the Documentation of the Research
EPA identified this study through a review of the public literature. No person has independently submitted the published article or any results of this research to EPA. Consequently, the requirements for the submission of information concerning the ethical conduct of completed human research contained in EPA regulations at 40 CFR part 26, subpart M do not apply.
Standards Applicable to EPA’s Reliance on the Research
The Agency’s rule (40 CFR part 26 subpart Q) defines standards for EPA to apply in deciding whether to rely on research—like this study—involving intentional exposure of human subjects. The applicable acceptance standards from 40 CFR part 26 subpart Q are these:
§26.1703. Except as provided in §26.1706, EPA must not rely on data from any research subject to this subpart involving intentional exposure of any human subject who is a pregnant woman (and therefore her fetus), a nursing woman, or a child.
§26.1704 EPA must not rely on data from any research subject to this section if there is clear and convincing evidence that: (1) The conduct of the research was fundamentally unethical (e.g., the research was intended to seriously harm participants or failed to obtain informed consent); or (2) The conduct of the research was deficient relative to the ethical standards prevailing at the time the research was conducted in a way that placed participants at increased risk of harm (based on knowledge available at the time the study was conducted) or impaired their informed consent.
EPA has submitted this study for review by the Human Studies Review Board (HSRB) because 40 CFR §26.1602 requires HSRB review for pre-2006 studies intended for EPA reliance that were conducted for the purpose of identifying or measuring a toxic effect. This study meets those criteria.
Compliance with Applicable Standards
All of the subjects in this study were postmenopausal women (mean age was 66±6 years). Thus, all of the subjects were adults and none were pregnant or nursing. EPA’s reliance on the research is therefore not prohibited by 40 CFR §26.1703.
With regard to 40 CFR §26.1704 (whether there was clear and convincing evidence that this research was either fundamentally unethical or deficient relative to the ethical standards prevailing at the time the research was conducted in a way that placed participants at increased risk of harm or impaired their informed consent), there is no relevant information in the published article. I tried several different approaches to locate records of an ethics review or any other information about the ethical conduct of this study, but I was not successful in that regard.
I attempted to obtain information about this study from the Swedish Medical Research Council, Sahlgrenska University Hospital, and the Regional Ethics Review Board for Gothenburg, but either received no response or was notified that there was no information available because of the date of this study.
Based on the absence of clear and convincing evidence that the research was fundamentally unethical or intended to harm participants, I conclude that reliance on the research is not prohibited by 40 CFR §26.1704(1). Based on the absence of clear and convincing evidence that the research was deficient relative to the prevailing ethical standards, I conclude that reliance on the research is not prohibited by 40 CFR §26.1704(2).
I find no barrier in law or regulation to reliance on MRID 49489102 in EPA actions taken under FIFRA or §408 of FFDCA. I defer to others for a full review of the scientific validity of this study. If it were determined not to have scientific validity, it would also not be ethically acceptable.
*This Memorandum was included (pages 10-14 of 20) in Background Material for HSRB Review of Hansson and Roos (1987) at http://fluoridealert.org/wp-content/uploads/epa.background-material-hanson-roos.2014.pdf
Notes from Fluoride Action Network
— if you are having trouble with blank pages in the above link, search for fluoride and this memorandum will appear.
— see also the December 30, 2014, Memorandum: Materials for Review by the EPA’s Human Studies Review Board for its Jan 14, 2015 Meeting
— we added the link to the above study by Hansson and Roos.