Draft Report of Quantitative Risk and Benefit Assessment of Consumption of Commercial Fish, Focusing on Fetal Neurodevelopmental Effects (Measured by Verbal Development in Children) and on Coronary Heart Disease and Stroke in the General Population: Section III, Scientific Basis for Risk and Benefit Assessment
January 15, 2009
This information is distributed solely for the purpose of pre-dissemination peer and public review under applicable information quality guidelines. It has not been formally disseminated by FDA. It does not represent and should not be construed to represent any agency determination or policy.
This section reviews results from research studies in humans(7) that are germane to evaluating the risks associated with methylmercury jointly with the benefits of commercial fish consumption(8). The research studies reviewed here focus on health endpoints for which there are reports in the scientific literature of statistical associations both between methylmercury and adverse effects and between fish consumption and beneficial effects. These are:
- Neurodevelopmental effects in the fetus from the mother's consumption of food resulting in prenatal exposure to methylmercury and to nutrients in fish.
- Neurodevelopmental effects in children from their own consumption of food resulting in postnatal exposure to methylmercury and to nutrients in fish. The central nervous system continues to develop after birth so an important question is whether children are more sensitive than adults to a neurotoxin such as methylmercury.
- Fatal coronary heart disease and stroke in the general population as a result of eating fish. Methylmercury has been implicated as a potential risk factor for coronary heart disease and stroke in some studies in limited populations outside of the United States. Fish and some nutrients in fish have been widely studied for their potentially beneficial effect on these same endpoints.
This report does not review research regarding neurological effects in the general population from postnatal exposure to methylmercury or consumption of fish. For neurological effects the scope of this report is limited to potential consequences to the developing nervous system.
FDA does not conduct primary research in humans on either the toxicity of methylmercury or the benefits for health of eating fish. The Agency relies on studies that are published in the peer reviewed literature. With respect to toxicity, The National Academies of Science's "Toxicological Effects of Methylmercury," published in 2000, offers a comprehensive evaluation of the scientific literature through that date (NRC 2000). Since then additional analyses of some of the same cohorts highlighted in the NAS review have been published, as have analyses of other cohorts. The goal of this Section is to provide the scientific basis for the risk and benefit assessment described later in this report as well as provide a context for interpreting the results of those analyses. Our review is not intended to serve as a substitute for reading the reports of the studies that have been published by the researchers or analyses of studies that have been published by others
Note that most of the studies discussed here have reported their findings in terms of total "mercury" (i.e, including molecular forms of that element that do not appear in fish in significant amounts, i.e., inorganic forms). Laboratory analyses for total mercury in hair and blood are easier and less costly to perform than analyses for methylmercury, the form of mercury that is primarily found in fish. For most studies it can be assumed that most of the total mercury found in hair has been methylmercury and that almost all the methylmercury has been from fish.
With respect to potential health benefits, there are a number of original (or primary) scientific studies on the health effects associated with consumption of fish or n-3 LC PUFA. The primary studies most relevant to the evaluation of the risks and benefits of fish consumption have been summarized and evaluated previously in a number of recent scientific reports and review articles (or secondary sources). Thus, the primary approach used to develop the benefits summary document accompanying this report (" Summary of Published Research on the Beneficial Effects of Fish Consumption and Omega-3 Fatty Acids for Certain Neurodevelopmental and Cardiovascular Endpoints") was to inventory these secondary sources and to highlight any findings related to the health effects of fish consumption and of the n-3 LC PUFA found in fish on cardiovascular disease and neurodevelopment. Research has addressed the possible association of fish or of n-3 LC PUFA consumption with numerous other health outcomes, including neuropsychiatric disorders (including depression and psychotic disorders), cognitive decline and Alzheimer's disease, neurodegenerative disorders, cancer risk reduction, and reduced risk of chronic degenerative diseases related to immune and auto-immune or musculo-skeletal function, acute macular degeneration and other visual impairments, although consideration of these outcomes is beyond the scope of this document. When available, the benefits summary document also identifies reports of quantitative dose-response relationships.
Studies on Neurological Endpoints
(a) Association between Fish Consumption and/or Omega-3 Fatty Acids and Neurodevelopmental Outcomes
A detailed discussion of the association of maternal fish consumption with infants' and children's visual and cognitive indicators of neurodevelopment can be found in the accompanying document, entitled "Summary of Published Research on the Beneficial Effects of Fish Consumption and Omega-3 Fatty Acids for Certain Neurodevelopmental and Cardiovascular Endpints." Below, we provide a brief summary.
Observational studies: In three cohort studies, children's visual function (Williams et al., 2001) and neurodevelopment (Daniels et al., 2004; Oken et al., 2005) were positively associated with mother's fish intake during pregnancy, with adjustment for covariates. The association with visual function is consistent with certain analyses of supplemented infant formula (Birch et al., 2005; Lauritzen et al., 2001; Morale et al., 2005; Uauy et al., 2003). Recent results estimated a positive, quantitative association between maternal fish consumption and children's developmental scores in Project Viva in the United States at three years of age (Oken et al., 2008a) and in the Avon Longitudinal Study of Parents and Children (ASPAC) cohort in the United Kingdom at eight years of age (Hibbeln et al., 2007a; Hibbeln et al., 2007b). The magnitude of the quantitative estimates from observational studies is considerably larger than estimates based on infant supplementation studies and a series of assumptions (Cohen et al., 2005a; Cohen et al., 2005c). The results of these studies within the context of the negative association with methylmercury is discussed in the next section.
A more detailed discussion of the studies that attempt to look at both fish consumption and methylmercury exposure is provided in the next section.
Randomized trials of maternal supplementation in pregnancy and lactation: Among the few available studies of maternal supplementation, women in the Helland et al. (2003) study were supplemented with fish or fish oil providing 1.2 grams of DHA per day during pregnancy and lactation and increased infant DHA blood levels were demonstrated biochemically (Eilander et al., 2007). Limitations included uncertain effect of the corn oil control supplement, the small subset of the population that received follow up IQ testing at age four years, and uncertain differences in background n-3 LC PUFA intake between Norwegian and U.S. women. However, the 4.1 point higher average K-ABC Mental Processing IQ scores of the children of fish oil supplemented mothers supports the plausibility of measurable neurodevelopmental benefits of maternal seafood consumption and gives one example of magnitude of dose-response. Additional maternal supplementation trials would be helpful to replicate this result, and to add features such as detailed background n-3 LC PUFA status, supplementation in pregnancy alone or including lactation, various levels of fish oil supplement dose, and several years of complete, planned follow up testing.
Randomized trials of infant formula supplementation: The complexity and inconsistency of the literature on supplementation of infant formula with DHA is a barrier to demonstrating the plausibility of measurable neurodevelopmental benefits for infants and children. The potential for estimating a quantitative dose-response from these data is limited. Among the factors that differed across the randomized trials were: infant population (preterm or term birth), timing of supplementation (beginning at birth or after period of breastfeeding; duration of a few months to one year), test formula composition (presence of arachidonic acid (AA); levels of DHA, AA and alpha-Linolenic acid (ALA)), additional breast fed comparison group, neurodevelopment outcome (vision, cognitive, general development, other), visual acuity testing (behavioral or electrophysiologic), neurodevelopment testing (global or targeted assessment), age at testing (early infancy to three years or older). Systematic reviews and meta-analyses evaluated the randomized trials in subgroups according to various study conditions, and generally found the evidence for neurodevelopmental benefit of DHA supplemented formula to be inconsistent and inconclusive (Lewin et al., 2005; Simmer 2001; Simmer and Patole 2004; Simmer et al., 2008a; Simmer et al., 2008b; Smithers et al., 2008). Studies were grouped differently in different systematic reviews, and newer studies were available for more recent reviews, making comparisons difficult across reviews.
The analysis of Lauritzen et al. (Lauritzen et al., 2001) concentrated on a single age at testing (four months) and identified formula composition and visual acuity method as likely sources of heterogeneity among trials. These authors recommended that future trials use conditions from previous positive trials, including DHA as 0.36 percent of lipids in test formula and electrophysiologic method for visual acuity testing. The meta-regression of Uauy et al (Uauy et al., 2003) quantified the dose-response for DHA equivalents in 12 comparisons from seven controlled trials of term infant visual acuity at four months of age (Table 3). Morale et al., (2005) analyzed visual acuity at age 12 months in studies from a single laboratory and found a linear dose-response for duration of supply of LC PUFA from formula supplemented with DHA as 0.36 percent of lipids, breastfeeding, or both (Table 12). Birch et al., (2005) designed a trial to carry out the Lauritzen et al. recommendations regarding DHA level in test formula and electrophysiological visual acuity as well as adequate sample size (greater than 20 per group). Supplemented infants had significantly better visual acuity at six, 17, 39 and 52 weeks of age and better stereoacuity at 17 weeks.
Most studies showed little evidence of a positive effect of supplemented formula on infant neurodevelopment using global tests, such as the Bayley scales. A few studies reported positive effects using more specific, focused developmental assessments, but these assessment methods were not adopted by other research groups (Willatts et al., 1998). The study of Birch et al. (1998) did find a positive effect of supplemented formula for four months using Bayley's MDI at 18 months of age. In a follow up at four years of age, infants supplemented with DHA plus AA had mean Wechsler Performance, Verbal and Full Scale IQ scores that were 4.4, 5.7 and 6.5 points higher, respectively, than scores of control infants (Birch et al., 2007). However, the statistical significance of this comparison was not tested directly but in a research design including a breast fed group and a DHA (with no AA) supplemented group. A secondary analysis of the IQ comparison for DHA plus AA supplemented and control infants from Birch et al. (2007) would show whether the result is statistically significant and if not significant, what sample size would be needed to replicate the results with adequate power.
Cohen et al. (2005a; 2005c) pooled the results of nine unique trials of supplemented formula and neurodevelopmental outcomes. Based on the average DHA level in supplemented formulas, the authors estimated an effect size of 4.6 IQ points for each one percent DHA (as percent of lipids) in infant formula (Table 9). In the supplemented formula of Birch et al. (2007), the DHA level was 0.36 percent, giving a Full Scale IQ effect size of 18 points (6.5/0.36) per one percent DHA in formula, considerably larger than the 4.6 point effect size of Cohen et al. (2005a; 2005c) Cohen and coauthors reported only a point estimate and did not state whether their result was significantly different from no effect.
(b) Association between Methylmercury Exposure and Neurodevelopmental Effects in the Fetus from Prenatal Exposure
Table IIIA-1 lists the major peer reviewed studies that explored the effect of prenatal exposure to methylmercury on neurodevelopment. The table is subdivided by the level of exposure. The first set of studies in this table is based on contamination incidents in Japan and Iraq. These incidents demonstrate that methylmercury can cause overt neurological abnormalities and even death when levels in the body approach and exceed 100 times more than average body levels in the United States (Harada et al., 1995; Marsh et al., 1987; McDowell et al., 2004). In the Minamata, Japan poisoning incident, methylmercury concentrations in fish ranged from 40 times to over 300 times higher than the average concentration in commercial fish in the U.S. marketplace today (Harada et al., 1995). The events provided evidence that an expectant mother's exposure to high amounts of methylmercury could result in neurological injury to her offspring even when the mother was not significantly affected (Harada et al., 1995; Marsh et al., 1987).
A number of research projects have investigated whether neurodevelopment in the fetus is being affected at much lower levels of exposure (than that seen in the Minamata population and in Iraq) as a result of day-to-day maternal consumption of fish. These investigations have been conducted in populations where fish is a mainstay of the diet and thus consumed much more frequently than it is on average in the United States (and as a result,exposure to methylmercury is also relatively higher). Daily fish consumption (and consumption of pilot whale in the Faroe Islands) results in concentrations of methylmercury in the bodies of these peoples that are well above those found in the vast majority of fish consumers in the United States and other countries with consumption patterns similar to those in the United States. The researchers anticipated that effects would reveal themselves as subtle differences in scores on neurodevelopmental tests between children who had been prenatally exposed to less methylmercury and those who had been prenatally exposed to more methylmercury within a study population (Marsh et al., 1995a; Myers et al., 2007).
Two large studies in the Seychelles and Faroe Islands produced apparently contradictory results. The Seychelles study found no consistent significant association between prenatal exposure to methylmercury and results on a wide battery of neurodevelopmental tests administered at several ages while the Faroe Islands study found adverse associations on a number of neurodevelopmental tests administered there (Grandjean et al., 1995 & 1998; Debes et al., 2006; Myers et al., 1995, 1997 & 2003; Davidson et al., 1995a & 1998). They found that in order to achieve body levels that are about 10-fold higher than average U.S. levels, the women in the Seychelles Islands study routinely ate about 12 fish meals per week (Shamlaaye et al., 1995). The researchers in the Faroe Islands concluded that the strongest associations they saw between methylmercury and neurodevelopmental test scores were the result of "stable," rather than "variable" exposures (Grandjean et al., 2003).
A considerable amount of attention was paid to possible explanations for the seemingly different outcomes in these studies (NRC 2000). A study in New Zealand had produced results similar to those in the Faroe Islands (Kjellström et al., 1986 & 1988). Since 2004, however, a significant number of studies have been published, many of which have involved populations in the United States and in countries where exposures to methylmercury are similar to those in the United States. These studies are described below.
(c) Observational Studies of both Fish Consumption and Methylmercury Exposure
One of the first such studies to look at both the beneficial effects of fish consumption while examining methylmercury exposure was from a cohort in the United Kingdom (Daniels et al., 2004). They found a beneficial association between maternal consumption of fish during pregnancy and neurodevelopmental test scores in their children but no adverse association between prenatal exposure to methylmercury in the fish and the same test scores. The authors stated that methylmercury exposures in their cohort were "low" (Daniels et al., 2004, page 398), with the comparison apparently being to much higher exposures in the Faroe Islands, where adverse effects had been reported (Daniels et al., 2004, page 400).
A number of studies since then have found a beneficial association between maternal fish consumption and test scores and, in addition, an adverse association between the methylmercury in the fish and the test scores (Oken et al., 2005; Oken at al., 2008; Hibbeln et al., 2007a ). In these studies, the methylmercury levels in the fish typically reduced some of the beneficial outcome associated with fish consumption but did not often eliminate the beneficial outcome entirely. In one study (Oken et al., 2005), the authors provided information by which the size of the beneficial fish contribution could be compared to the size of the adverse methylmercury contribution. Using such a calculation, each additional weekly fish serving was associated with an average increase of four points on a test of "visual recognition memory" (VRM) while the methylmercury in each additional serving was associated with an average decrease of 1.28 points on this test. (9)
Four analyses suggested that eating more than 12 ounces of fish per week may convey more benefits than eating less than 12 ounces (Oken et al., 2005; Oken et al., 2008; Hibbeln et al., 2007a; Oken et al., 2008a) even though this finding could include some reduction from methylmercury as described above. In Oken et al. (2005), those who ate more than two servings of fish per week had infants with VRM scores that were 12 points higher than infants whose mothers consumed two or fewer weekly servings; however, those who ate the highest amounts of fish and had lower hair mercury levels had infants with higher VRM scores than infants whose mothers ate similar amounts of fish but had higher hair mercury levels. Similar findings were reported in Oken et al. (2008). Collectively, the results suggest that the higher the methylmercury in the fish, the greater the reduction in benefits, to the point where the net effect could even be adverse.
The results from the earlier New Zealand and Faroe Islands studies could be interpreted to be consistent with those results. In the New Zealand study, adverse effects were seen in a population that apparently ate a lot of fish high in methylmercury (shark) (Kjellström et al., 1986). Although the overall net effect from eating fish was not measured (the reported association was between the methylmercury in the fish and neurodevelopmental test scores), the results from this study suggest that the net effect can become adverse when the diet includes enough high methylmercury fish.
A similar conclusion can be drawn from the Faroe Islands study. There, more methylmercury came from eating pilot whale than from eating fish (Grandjean et al., 1999). The fish primarily consumed in the Faroe Islands (cod) were low in mercury, with a reported average concentration of 0.07 ppm (Weihe et al., (1996, page 142). With the methylmercury from the pilot whale added to the diet, however, it would have been equivalent to eating fish with much higher concentrations of methylmercury. Structural equation modeling of neurodevelopmental test data at seven and 14 years of age from the Faroe Islands showed that, after mutual adjustment for both variables, there was an independent, positive association with maternal fish intake as well as a negative association with maternal mercury exposure (Budtz-Jørgensen et al., 2007). Preliminary results from the Seychelles nutrition cohort suggested that children's developmental tests were positively associated with maternal n-3 LC PUFA blood levels and negatively associated with maternal hair mercury (Myers et al., 2007). These associations were stronger when mutually adjusted for the other variable.
|Exposure Level||Location||Outcome Measures||Findings|
|Where Exposures to Methylmercury Approach (and Exceed) 100x Average U.S. Exposures||Japan (Harada et al., 1995)||All neurological effects reported from the poisoning event||
Adverse neurological effects ranging from mild to severe and including fatal.
Fetus often more severely affected than the mother.
|Iraq (Marsh et al., 1987)
Study pop.: 81
Significant adverse association found between prenatal exposure and milestone and examination results.
Fetus often more severely affected than the mother.
|Where Exposures to Methylmercury Are Roughly 10x Average U.S. Exposures||New Zealand (Kjellström et al., 1986 & 1988)
--38 at age 4
--61 at age 6("high exposure" part of the study
|Neurodevelopmental tests at ages 4 & 6, including IQ at age 6||Significant adverse associations found between prenatal exposure and some results, including IQ.|
|Faroe Islands (Grandjean et al., 1995 & 1998; Debes et al., 2006)
Study pop. : 900+
|--Neurodevelopmental milestones: ages of first sitting, creeping, standing
--Battery of neurodevelopmental tests at ages 7 & 14 years
|Significant adverse associations found between prenatal exposure and some results.|
|Faroe Islands (Budtz-Jorgensen et al., 2007)
Study pop.: 900+
|Reanalysis of results from battery of neurodevelopmental tests at ages 7 & 14 years of age.||
|Seychelles Islands (Myers et al., 1995, 1997 & 2003; Davidson et al., 1995a & 1998)
Study pop. : 700+
|--Neurodevelopmental milestones: ages of first walking and talking
--Battery of neurodevelopmental tests at ages 6.5 mo., 19 mo., 29 mo., 66 mo., & 9 years (including IQ)
|No consistent significant adverse associations found between prenatal exposure and test results.|
|Where Exposures to Methylmercury are in the Range of U.S. Exposures||U.K. (Daniels et al., 2004)
Study pop.: 7,421
|Neurodevelopmental tests at ages 15 & 18 months||No significant adverse association found between prenatal exposure and test results|
|U.S. (Oken et al., 2005)
Study pop.: 135
|Test of visual recognition memory at ages 5.5 - 8.4 months||
|U.S. (Oken et al., 2008)
Study pop.: 341
|Neurodevelopmental tests at 3 years of age.||
|Poland (Jedrychowski et al., 2006)
Study pop.: 233
|Neurodevelopmental tests at 1 year of age.||Significant adverse association found between prenatal exposure and test results.|
|Poland (Jedrychowski et al., 2007)
Study pop.: 374
|Neurodevelopmental tests at 2 & 3 years of age.||No significant adverse association found between prenatal exposure and test results. The significant adverse association seen at age 1 (above) could not longer be found.|
|U.K. (Williams et al., 2001)
Study pop.: 435
|Stereoscopic vision at age 3.5 years||Significant beneficial association found between maternal consumption of oily fish and stereoscopic vision.|
|U.K. (Hibbeln et al., 2007a)
Study pop. : 9,000
|Neurodevelopmental tests ages 6 mos. Through 8 years, including IQ||
Greater fish consumption, including above 2 servings per /week, associated with higher scores including IQ.
NOTE: Methylmercury exposure was subsequently estimated by the authors. They concluded that methylmercury reduced the size of the benefit from fish somewhat but that the net effect remained beneficial.
|United States (Lederman et al., 2008)
Study pop.: 329
|Bayley Scales of Infant Development II at 12, 24, and 36 months of age; Wechsler Preschool and Primary Scale of Intelligence at 48 months of age.||This study was initially designed to study outcomes from contamination from the World Trade Center collapse in N.Y. The study reported that mercury was associated with lower scores but that fish consumption during pregnancy was associated with higher scores.|
|Denmark (Oken et al., 2008a)
Study pop.: 25,446
|Various developmental milestones at 6 & 18 months of age||Significant beneficial associations found between higher maternal fish consumption and attainment of developmental milestones.|
(d) Neurodevelopmental Effects in Children from Postnatal Exposure
Children may be especially sensitive to the effects of neurotoxins because their nervous systems are still developing.
Whether children are experiencing adverse effects as a consequence of exposure to methylmercury after birth has been studied in the Faroe and Seychelles Islands. The studies in both locations have reported no adverse effects in children who had levels of exposure that are substantially higher than average U.S. exposures. The two studies reported improvements on neurological tests scores as the children's exposure to methylmercury (as measured by blood and hair samples from the children) increased. Presumably these results were not due to methylmercury but to increases in postnatal fish consumption.
In an early phase of their study, the Faroe Islands researchers looked for an association between postnatal mercury exposure and delays in the developmental milestones of first sitting, creeping and standing (Grandjean et al., 1995). They found that infants who achieved these milestones the earliest had the highest hair mercury levels at 12 months of all those in the study population. The researchers noted that these children had also experienced the longest breastfeeding and they hypothesized that the contents of mother's milk, including n-3 long-chain fatty acids, might have been responsible for their early development.
The Faroe Islands researchers also addressed postnatal exposure at a later age. In their discussion of neurological test results when the children were 14 years old, they state that "Postnatal methylmercury exposure had no discernible effect" and that this outcome, among others, was similar to those obtained when the children were seven years old. They also indicate that they saw improvements, i.e., "many coefficients suggesting effects in the direction opposite to expectation," although they do not appear to have been statistically significant (Debes et al., 2006).
The Seychelles research team reported a similar outcome. In its paper on outcomes at 66 months of age, the team describes dividing the study population into five groups based on the children's mercury hair levels. The group with the highest mean mercury hair level, 14.9 ppm, scored slightly better on four of six neurological development scores than the group with the lowest mean of 2.2 ppm (Davidson et al., 1998). The NHANES survey has shown a mean of 0.22 ppm for U.S. children one to five years of age. This average is nearly 1/70th the highest mean level in the Seychelles with slightly improved scores (McDowell et al., 2004, p. 1,167).
The Daniels et al. (2004) study of ALSPAC data from the United Kingdom reported an association between increases in children's fish consumption and small but statistically significant improvements in scores on neurodevelopmental tests within a study population of slightly over 7,400. Methylmercury levels in the children were not measured as they were in the Seychelles and Faroe Islands, so it is necessary to assume that increases in postnatal fish consumption in this study population were accompanied by increases in methylmercury exposure.
The U.K. children were younger (15 and 18 months) than the children in the Seychelles (66 months) and Faroe Islands (14 years) when they were tested for behavioral performance. The beneficial association between children's fish consumption and test scores reported by Daniels et al. (2004) is consistent with the results in the Seychelles and Faroe Islands at the later ages, although exposure to methylmercury in the Daniels et al. cohort was lower.
A related question about children is whether infants can be adversely affected by methylmercury in mother's milk. One way of considering this question is to examine whether an infant's postnatal exposure through lactation will be the same as its prenatal exposure. The transport of methylmercury from maternal blood into human milk is less efficient than the transport across the blood-brain and blood-placenta barriers. The ratio between methylmercury in maternal blood serum and methylmercury in maternal milk is small and results in very low concentrations in maternal milk. Consequently, if a mother continues to eat the same types and amounts of fish during lactation as she did while pregnant, the infant's exposure to methylmercury can be expected to drop as compared to what occurs in utero (Björnberg et al., 2005; Dorea 2004; FAO/WHO JECFA, 2007). The limited transfer of methylmercury into maternal milk is consistent with the fact that adverse associations between methylmercury and neurodevelopment have been reported only for prenatal methylmercury exposure but not for postnatal exposure.
Studies on Coronary Heart Disease and Stroke
(a) Association between Fish Consumption or Omega-3-Fatty Acids and Cardiovascular Disease
Several lines of evidence, taken together, suggest the association of fish or n-3 LC PUFA consumption and decreased Coronary Heart Disease (CHD) risk:
- Primary and secondary prevention, randomized clinical trial of fish oil consumption. The recently published large-scale clinical trial called the Japan EPA Lipid Intervention Study (JELIS) from Japan included over 18,000 men and women (Yokoyama et al., 2007). Almost 15,000 participants had no record of coronary artery disease (primary prevention). Results showed a 19 percent decrease in major coronary events (fatal plus nonfatal) for all subjects, a 19 percent decrease for secondary prevention subjects and an 18 percent decrease for primary prevention subjects. The decrease in risk was similar in magnitude for primary and secondary prevention, but was not statistically significant for primary prevention alone (p = 0.13). For the full study and for both subgroups, there was no significant decrease in sudden cardiac death or coronary death alone, probably reflecting that the high baseline fish intake in Japan is above a possible threshold for effect on risk of sudden death or CHD death.
- Secondary prevention, randomized clinical trials of fish or fish oil consumption. The large, well-conducted secondary prevention trial, GISSI, included over 10,000 men and found a 15 percent decrease in all deaths plus nonfatal heart attacks and strokes, a 26 percent decrease in cardiovascular deaths plus nonfatal heart attacks and strokes and a 45 percent decrease in sudden death, all significant (GISSI 1999; Marchioli et al., 2002) Results of the DART1 study were consistent with GISSI, but results differed for the poor quality DART2 study (Burr et al., 2003; Burr et al., 1989).
- Meta-analyses of randomized controlled trials of fish or fish oil consumption. Mozaffarian and Rimm (Mozaffarian and Rimm 2006) conducted a meta-analysis including five randomized controlled trials and 15 prospective cohort studies of fish or fish oil intake and CHD death among >300,000 subjects. There was a significant, 17 percent decrease in total CHD mortality. A total 36 percent reduction in risk was estimated for intakes of 250 mg/day EPA/DHA.
- Observational studies of blood levels of n-3 LC PUFA and CHD risk. As summarized by (SACN 2004) and others, additional evidence for the cardiovascular benefits of fish and fish oil consumption is provided by several cohort or case control studies that found decreased CHD risk associated with higher blood levels of DHA and EPA. SACN stated that, "Taken together, these data support the hypothesis that n-3 LC PUFA are responsible for the observed inverse association between fish consumption and sudden cardiac death."
- Meta-analyses of observational studies of fish consumption and risk of cardiovascular disease. There are several meta-analyses of observational studies of fish consumption and risk of CHD or stroke with fairly consistent results among the meta-analyses. The prospective studies of CHD death included more than 200,000 men and women and the prospective studies of stroke also included more than 200,000 men and women. For example, the meta-analyses of He et al (He et al 2004a; He et al 2004b) found a 15 percent decreased risk of CHD death and a 13 percent decreased risk of stroke associated with fish intake once per week compared with less than once per month.
- A meta-analysis (Studer et al 2005) of 97 studies, with 137,140 individuals in intervention and 138,976 individuals indicted that the benefits of n-3 LC PUFAS were comparable to (or greater) than the benefits of statins for overall mortality.
A detailed discussion discussion of these studies is available in the accompanying document entitled "Summary of Published Research on the Beneficial Effects of Fish Consumption and Omega-3 Fatty Acids for Certain Neurodevelopmental and Cardiovascular Endpoints".
(b) Association between Methylmercury Exposure from Fish Consumption and Cardiovascular Disease Toxic Effects
The extreme exposures to methylmercury that occurred in the poisoning events in Japan and Iraq do not appear to have resulted in CHD. In the Japan poisoning events, nine percent of deaths among chronic patients who died from 1975 to 1982 were from cardiac failure as compared to the Japanese national average of 21.3 percent for the same time period (Harada 1995, page 18; Chan and Egeland 2004, page 69). In the Iraq poisoning event, involvement of the cardiovascular system was reported to be rare (Bakir et al., 1973), however there has been no long-term follow-up of this endpoint from that event.
A relationship between methylmercury and CHD and stroke was initially studied in Finland beginning in 1984 as part of a search for an explanation for why men in eastern Finland were experiencing one of the highest mortality rates in the world from cardiovascular disease even though they tended to eat a lot of fish (mainly lean lake fish that were low in omega-3 fatty acids and selenium). Studies conducted around the world have pointed to an association between fish consumption, or the consumption of omega-3 fatty acids that are a natural component of fatty fish, and a reduced incidence of CHD. Why did eastern Finland appear to be so different in that respect and did the difference involve methylmercury?
The researchers found an association between methylmercury from nonfatty freshwater fish and the incidence of CHD and stroke in eastern Finland (Salonen et al., 1995). Results were first published in 1995, with follow-up results published in subsequent years.
We are aware of subsequent studies that looked for an association between methylmercury and cardiovascular endpoints in four additional populations: (1) Swedish women in a city in southwestern Sweden (Ahlqwist et al., 1999); (2) Swedish women and men in northern Sweden (Hallgren et al., 2001); (3) individuals from eight European countries and Israel (Guallar et al., 2002); (4) U.S. men (Yoshizawa et al., 2002). The findings are mixed and there are questions about how to interpret the results from each study. The study of the eight European subpopulations plus Israel reported an association between methylmercury and increased CHD risk but the remaining three studies did not, although the U.S. study reported a non-statistically significant association in one aspect of the study. One of the Swedish studies looked for an association between methylmercury and stroke but found none.
In contrast to the relatively limited data from these five populations on possible associations between methylmercury and CHD and stroke, there exist a substantial quantity of data, collectively involving hundreds of thousands of individuals, from many studies that have looked for an association between eating fish (although not typically differentiated by species), or from ingesting omega-3 fatty acids, and risk of CHD or stroke morbidity and mortality. Although these studies did not measure methylmercury levels in the individuals who participated in them, it is reasonable to assume that the fish contained methylmercury. Our risk and benefit assessment utilizes data from these studies, as explained in Section IV of this report and Appendix A.
Below are tables that summarize: (a) the studies involving methylmercury; and (b) the studies involving "fish." Because the fish studies have been the subject of meta-analyses that consolidated the results from each study, the "fish" table focuses on the meta-analyses and thus also presents the results in a consolidated format.
|Study||Population and follow-up||Exposure measure(s)||Control for n-3 exposure||CHD outcome||Findings for MI and CHD death|
1833 (Salonen) or 1871 (Rissanen and Virtanen) men in eastern Finland 42-60 yrs with no CHD, CVD stroke history, claudication, or cancer at baseline.
Follow-up: 7 yrs (Salonen), 10 yrs (Rissanen), 14 yrs (Virtanen)
|Hair Hg (µg/g),
fish intake (g/day)
Yes (Rissanen, Virtanen)
Salonen: Acute MI, CHD death, CVD death, and all-cause death
Rissanen: Acute MI, acute chest pain
Virtanen: Acute coronary event, CHD death, CVD death, and all-cause death
Salonen: CHD mortality: RR=1.21 (1.04-1.40) per µg/g Hg in hair Total MI: RR=1.07 (0.97-1.18) per µg/g Hg in hair.
Virtanen: CHD mortality: Highest hair Hg tertile RR=1.21 (0.71-2.06) vs lowest tertile, p for trend 0.4.
|Ahlqwist(1999)||1462 Swedish women aged 38-60 at baseline. Follow-up: 24 years||Serum Hg||No||MI||When controlled for age and education, p > 0.2 for MI, p=0.144 for fatal MI. Correlation <0, suggesting higher Hg exposure reduces risk|
|Hallgren(2001)||78 first-ever MI cases from Northern Sweden matched to 156 controls on gender, age, date of health survey, region||Blood Hg||Yes||First MI||No consistent association with Hg exposure|
|Guallar (2002)||684 first-ever MI cases matched with 724 controls. Population included men ≤70 yrs from any of 8 European countries or Israel||Toenail Hg||Yes||First MI||Highest Hg exposure quintile RR=2.16 (1.09-4.29) vs lowest Hg exposure quintile|
|Yoshizawa (2002)||470 cases and 464 controls drawn from 33,737 male health professionals with no cancer, MI, angioplasty at baseline. Follow-up: 5 yrs||Toenail Hg||Yes||CHD (fatal CHD, nonfatal MI, coronary-artery bypass surgery, angioplasty)||No consistent association with Hg exposure. Highest Hg exposure quintile RR=1.03 (0.65-1.65) vs lowest Hg exposure quintile|
|Study||Health Outcome||Number of study populations||Number of subjects||Follow-up time||Results|
|He et al., 2004a||Coronary heart disease death||13*||222,364||11.8 years||15% decrease in risk of CHD mortality associated with fish intake once per week, 23% decrease in risk with fish intake 2 to 4 times per week, 38 % decrease in risk with fish intake 5 or more times per week, all statistically significant. Each 20-g/d increase in fish intake related to statistically significant 7% lower risk of CHD mortality.|
|Whelton et al., 2004||Coronary heart disease death||13||215,705||5 to 30 years||Fish consumption versus little to no fish consumption associated with statistically significant 17% decrease in risk of fatal CHD.|
|Total coronary heart disease||Fish consumption versus little to no fish consumption associated with statistically significant 14% decrease in risk of total CHD|
|Total coronary heart disease cohorts||7||190,262||5 to 19 years|
|Total coronary heart disease case control||5||4,964||------|
|König et al., 2005||Coronary heart disease death||7||157,835||6 to 30 years||Consuming small quantities of fish associated with 17% reduction in CHD mortality risk, with each additional serving per week associated with further reduction in this risk of 3.9%, both statistically significant.|
|Nonfatal coronary heart disease||3||133,493||6 to 16 years||Small quantities of fish consumption compared with no consumption associated with 27% reduced risk of nonfatal heart attack, but additional fish consumption conferred no incremental benefits.|
|He et al., 2004b||Stroke||9||200,575||12.8 years||13% decreased risk of stroke associated with fish intake once per week, 18% decreased risk with fish intake 2 to 4 times per week, 31% decreased risk with fish 5 or more times per week, all statistically significant.|
|Bouzan et al., 2005||Stroke||Any fish consumption associated with statistically significant 12% decreased risk of stroke and each additional one serving per week may be associated with an additional 2.0% decreased risk.|
|Stroke cohorts||4||129,767||12 to 30 years|
|Stroke case control||1||823||-------|
|Included studies are cohort studies unless otherwise noted.
*11 independent studies
(c) Blood Pressure in Children Through Age 15 (Seychelles and Faroe Islands)
The researchers in the Faroe Islands reported that at seven years of age, the boys in the study group showed an association between prenatal exposure to methylmercury and increased blood pressure, although the blood pressure was not elevated beyond normal ranges (Grandjean et al., 2004). When checked again when the children were 14 years of age, the association was no longer observed.
In the Seychelles Islands, Thurston et al. (2007) measured blood pressure at ages 12 and 15 years. They found no association between prenatal exposure to methylmercury and increased blood pressure at age 12, but at 15 years they found an association between prenatal exposures and increased diastolic blood pressure in boys. Thurston et al. (2007) was unable to identify a biological reason for an association that only involves diastolic blood pressure in boys at 15 years. They advocated further study, but concluded that their finding "does not suggest a consistent association between methylmercury and blood pressure" (Thurston et al., 2007, page 928). They noted that elevated blood pressure was not a major symptom in the extreme poisoning events in Japan and Iraq.
(7) For a review of the animal data on methylmercury we refer the reader to the Toxicological Profile on Mercury performed by the Agency for Toxic Substances and Disease Registry (ATSDR). This document contains the conclusion that "animal studies…provide irrefutable evidence that the central and peripheral nervous systems are target organs for organic mercury-induced toxicity" (ATSDR 1999, page 137). Animal data in support of an effect of methylmercury on cardiovascular effects is sparse (ATSDR 1999, see page 107).
(8) Section IV of this report identifies the studies that were used as the basis of the dose-response functions used in the risk/benfit analysis. These dose-response functions estimate the likelihood and magnitude of an effect at various "doses," or exposures to methylmercury, fish, or the combination of the two, i.e., the "net effect."
(9) The authors reported that an increase of 1.0 ppm in maternal hair mercury was associated with a decrement in VRM score of 7.5 points. In order to compare size of gains from fish (4 points per each additional weekly fish serving) against size of losses from methylmercury, it is necessary to calculate the average loss per fish serving. This can be done by calculating how many weekly fish servings had to be consumed in order to achieve an increase of 1.0 ppm in maternal hair mercury in this cohort. According to the authors, each weekly fish serving resulted in an increase of 0.17 ppm in maternal hair mercury. Dividing 0.17 ppm into 1.0 ppm reveals that 5.88 weekly fish meals are needed to achieve an increase of 1.0 ppm. Dividing 5.88 weekly fish meals into 7.5 VRM points lost (per each 1.0 ppm) results in 1.28 VRM points lost per weekly fish meal due to methylmercury.
(10) (NOTE: the studies actually measured total mercury but we assume that the results apply to methylmercury, the organic form found in fish.)