JAMA Fish Intake and Health Oct 06

7/29/2019 JAMA Fish Intake and Health Oct 06

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CLINICIANS CORNERCLINICAL REVIEW

Fish Intake, Contaminants, and Human HealthEvaluating the Risks and the BenefitsDariush Mozaffarian, MD, DrPH

Eric B. Rimm, ScD

SINCE THE PUBLICATION OF PIO-neering studies demonstratinglow rates of death from coro-nary heart disease (CHD)

among Greenland Eskimos,1 fish(usedhereinto refer to finfish or shellfish) hasbeen considered a healthy food. Dur-

ing ensuing years, evidence from sev-eral researchparadigmsincluding ani-mal-experimental, observational, andclinical studiesfurther supported thishypothesis and identified 2 long-chain n-3 polyunsaturated fatty acids(n-3 PUFAs), eicosapentaenoic acid(EPA) and docosahexaenoic acid(DHA), as the likely active constitu-ents.2-20 DHAalsoappears important forneurodevelopmentduringgestation andinfancy.21-26 Conversely, concern hasarisen over potential harm from mer-

cury, dioxins, and polychlorinatedbiphenyls (PCBs) present in some fishspecies.27-34 The public is faced withseemingly conflicting reports on therisks and benefits of fish intake, result-ing in controversy and confusion overtheroleof fish consumption ina healthydiet.35,36 To elucidate the relative risksand benefits, we reviewed the scien-tific evidence for adverse and benefi-cial health effects of fish consumption.

EVIDENCE ACQUISITION

Identification of Studies

A myriad of exposures and outcomeshave been related to fish consump-tion; we focused on populations and

topics for which evidence and con-cer n ar e g r eatest. W e sear chedMEDLINE, governmental reports, andsystematic reviews and meta-analyses

to identify reports published throughApril2006 evaluating (1) intake of fishor fish oil and risk of cardiovascularevents and mortality, (2) effects of me-thylmercury and fish oil on early neu-rodevelopment, (3) risks of methyl-mercury for cardiovascular andneurologic outcomes in adults, and (4)health risks of dioxins andPCBs in fish.

MEDLINE search terms were (Fishor n-3 PUFA or omega-3) and (coro-nary or cardiac or cardiovascularor mor-

See also Patient Page.

CME available online atwww.jama.com

Author Affiliations: Channing Laboratory, Depart-

ment of Medicine, Brigham and Womens Hospital,andHarvardMedicalSchool; andDepartments of Epi-demiology and Nutrition, Harvard School of PublicHealth, Boston, Mass.Corresponding Author: Dariush Mozaffarian, MD,DrPH,Harvard School of Public Health, 665 Hunting-ton Ave, Bldg 2, Room 315, Boston, MA 02115([email protected]).ClinicalReview Section Editor: Michael S. Lauer, MD.We encourage authors to submit papers for consid-eration as a Clinical Review. Please contact MichaelS. Lauer, MD, at [email protected].

Context Fish (finfish or shellfish) may have health benefits and also contain con-taminants, resulting in confusion over the role of fish consumption in a healthy diet.

Evidence Acquisition We searched MEDLINE, governmental reports, and meta-analyses, supplemented by hand reviews of references and direct investigator con-tacts, to identify reports published through April 2006 evaluating (1) intake of fish orfish oil and cardiovascular risk, (2) effects of methylmercury and fish oil on early neu-rodevelopment, (3) risks of methylmercury for cardiovascular and neurologic out-comes in adults, and (4) health risks of dioxins and polychlorinated biphenyls in fish.We concentrated on studies evaluating risk in humans, focusing on evidence, whenavailable, from randomized trials and large prospective studies. When possible, meta-

analyses were performed to characterize benefits and risks most precisely.

Evidence Synthesis Modest consumption of fish (eg, 1-2 servings/wk), especiallyspecies higher in the n-3 fatty acids eicosapentaenoic acid (EPA) and docosa-hexaenoic acid (DHA), reduces risk of coronary death by 36% (95% confidence in-terval, 20%-50%; P.001) and total mortality by 17% (95% confidence interval, 0%-32%; P=.046) and may favorably affect other clinical outcomes. Intake of 250 mg/dof EPA and DHA appears sufficient for primary prevention. DHA appears beneficialfor,and low-level methylmercury may adversely affect, early neurodevelopment.Womenof childbearing age and nursing mothers should consume 2 seafood servings/wk, lim-iting intake of selected species. Health effects of low-level methylmercury in adultsare not clearly established; methylmercury may modestly decrease the cardiovascularbenefits of fish intake. A variety of seafood should be consumed; individuals with veryhigh consumption (5 servings/wk) should limit intake of species highest in mercurylevels. Levels of dioxins and polychlorinated biphenyls in fish are low, and potential

carcinogenic and other effects are outweighed by potential benefits of fish intake andshould have little impact on choices or consumption of seafood (women of childbear-ing age should consult regional advisories for locally caught freshwater fish).

Conclusions For major health outcomes among adults, based on both the strengthof the evidence and the potential magnitudes of effect, the benefits of fish intake ex-ceed the potential risks. For women of childbearing age, benefits of modest fish in-take, excepting a few selected species, also outweigh risks.

JAMA. 2006;296:1885-1899 www.jama.com

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ders,41,42 and asthma or inflammatorydisorders43,44) were not reviewed inthis report.

EVIDENCE SYNTHESIS

Benefits of Fish Intake

Cardiovascular Outcomes. Deathfrom CHDie, documented or sus-pected fatal myocardial infarctionand sudden deathie, a suddenpulseless condition of presumed car-diac etiologyare clinically definedentities often sharing the final com-mon pathway of ventricular arrhyth-mia, often ischemia-induced ventricu-lar fibrillation. The evidence fromprospective studies and randomizedtrials2-4,6-17,45-51 suggests that consump-tion of fish or fish oil lowers risk ofC H D d e a t h a n d s u d de n d e a t h

(FIGURE 1 and FIGURE 2). Across dif-ferent studies (Figure 1), comparedwith little or no intake, modest con-sumption (250-500 mg/d of EPAand DHA) lowers relative risk by25% or more. Higher intakes do notsubstantially further lower CHD mor-tality, suggesting a threshold ofeffect.52 Pooling all studies, this pat-tern was clearly evident (Figure 2).At intakes up to 250 mg/d, the rela-tive risk of CHD death was 14.6%lower (95% confidence interval [CI],

8% to 21%) per each 100 mg/d ofEPA and DHA, for a total risk reduc-tion of 36% (95% CI, 20% to 50%).At higher intakes, little additionalrisk reduction was present (0.0%change per each 100 mg/d; 95% CI,0.9% to 0.8%). This thresholdeffect explains findings among Japa-nese populations,17,50 in whom highbackground fish intake (eg, median900 mg/d of EPA and DHA50) is asso-ciated with very low CHD death rates(eg, 87% lower than comparable

Western populations

9,17

), and addi-tional n-3 PUFA intake predicts littlefurther reduction in CHD death;thus, m o st o f the po pul ati o n i salready above the threshold for maxi-mum mortality benefits. Comparingdifferent types of fish, lower riskappears more strongly related tointake of oily fish (eg, salmon, her-

ring, sardines), rather than lean fish(eg, cod, catfish, halibut).10,15 Fishintake may modestly affect other car-diovascular outcomes, but evidenceis not as robust as for CHD death(TABLE 1).17,50,53-66

n-3 PUFAs influence several cardio-vascular risk factors.18,19,43,49,50,60-75,79-84 Ef-fects occur within weeks of intake andmay result from altered membrane flu-idity and receptor responses followingincorporation of n-3 PUFAs into cellmembranes76,77 anddirectbinding of n-3PUFAs to intracellular receptors regu-lating gene transcription.78 The hetero-geneity of the effects of fish or fish oilintake on cardiovascular outcomes islikely related to varying dose and timeresponses of effects on the risk factors

(FIGURE 3). At typical dietary intakes,antiarrhythmic effects predominate, re-ducing risk of sudden death and CHDdeath within weeks. At higher doses,maximum antiarrhythmic effects havebeen achieved, but other physiologic ef-fects may modestly impact other clini-cal outcomes (possibly requiring yearsto produce clinical benefits). For in-

stance, nonfatal myocardial infarctionmay not be significantly affected bylower doses or shorter durations of in-take but may be modestly reduced byhigher doses or prolonged intake (eg,1.8 g/d for 5 years17).

Heterogeneity of clinical effects mayalso be related to differing pathophysi-ologies of the clinical outcomes. For in-stance, disparate pathophysiologies ofprimary ventricular fibrillation (oftenischemia-induced) vs recurrent ven-triculartachyarrhythmias (ectopic or re-entrant) may explain stronger effects ofn-3 PUFAs on the former. Similarly, bio-logical differences in development ofatherosclerosis vs acuteplaque rupture/thrombosis vs arrhythmia would ac-count for heterogeneous effects of n-3

PUFAs on plaque progression vs non-fatal myocardial infarction vs CHDdeath. Consumption of fish may dis-place that of other foods, such as meatsor dairy products, in the diet. How-ever, this likely accounts for little of theobserved health benefits, because foodsreplaced would be highly variableamong individuals and across cul-

Figure 2. Relationship Between Intake of Fish or Fish Oil and Relative Risks of CHD Death inProspective Cohort Studies and Randomized Clinical Trials

0 500 1000 1500 2000 2500 3000

EPA+ DHA Intake mg/d

1.2

0.4

0.6

0.8

1.0

0.2

RelativeRisk

The relationship between intake of fish or fish oil and relative risk of coronary heart disease (CHD) death in apooled analysis of the prospective studies and randomized trials shown in Figure 1, evaluated nonparametri-cally using restricted cubic splines38,39 and adjusted for each within-study relationship. Given the much higherreferencegroupintakes in some studies, thereference relative riskwas scaledby 0.7for studies with referencegroup intakes between 150-500 mg/d of eicosapentaenoic acid (EPA)docosahexaenoic acid (DHA) (n= 5)and by 0.6 for studies with reference group intakes 500 mg/d (n= 1) based on spline relationships prior toincluding these studies; exclusion of these studies, or of the few groups with intakes 1000 mg/d, had littleeffect on the pooled spline relationship. A significant threshold effect ( P.001) was evident at intake of 250mg/d: between 0 and 250 mg/d, mortality risk was lower by 14.6% (95% confidence interval [CI], 8% to21%) per each 100-mg/d greater intake (total risk reduction, 36%; 95% CI, 20% to 50%; P.001), while athigherintakes, riskwas notfurtherlowered (0.0% changeper each 100mg/d; 95%CI, 0.9% to 0.8%; P=.94).*Relative risks in the control and intervention groups (for randomized trials) or relative risks in the referencegroup and multivariable-adjusted relative risks in the comparison groups (for cohort studies).

FISH INTAKE, CONTAMINANTS, AND HUMAN HEALTH




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tures, and modest intake of such foodsis not associated with CHD risk.85

Total Mortality. n-3 PUFAs moststrongly affect CHD death5,9,14-16,18 andare unlikely to affect appreciably othercauses of mortality. Effects on totalmor-

tality in a population would thereforedependon theproportion of deaths dueto CHD, ranging from one quarter ofdeaths in middle-age populations86 toone half of deaths in populations withestablishedCHD.9 Thus, givena36%reduction in CHD death (Figure 2), in-take of fish or fish oil would reduce totalmortality by between 9% (36% re-duction25% CHD deaths) to18%(36% reduction50% CHD deaths), oran average of14% in mixed popula-tions. This is consistent with a meta-analysis of randomized trials through

20033,9,51,56,57,87-93 that found a nonsig-nificant 14% reduction in total mortal-ity with n-3PUFAs (pooled relative risk,0.86; 95% CI, 0.70 to 1.04).94When weadded additional placebo-controlled,double-blind, randomized trials60-62 per-formed since 2003, marine n-3 PUFAsreduced total mortality by 17% (pooledrelativerisk, 0.83; 95% CI, 0.68 to 1.00;P =.046) (FIGURE 4). This can be com-pared to effects of statins on total mor-talitya 15% reductionin a meta-analysis of randomized trials (pooled

relative risk, 0.85; 95% CI, 0.79 to0.92).95

Neurologic Development. DHA ispreferentially incorporated intothe rap-idly developing brain during gestationand the first 2 years of infancy, concen-trating in gray matter and retinal mem-branes.26 Infants can convert shorter-chain n-3 fatty acids to DHA,96 but itis unknown whether such conversionis adequate for the developing brain inthe absence of maternal intake ofDHA.22,25

Effects of maternal DHA consump-tion on neurodevelopmenthave been in-vestigated in observational studies andrandomized trials, with heterogeneity inassessedoutcomes (visual acuity, globalcognition, specific neurologic do-mains) and timing of DHA intake (ges-tational vs nursing). In a meta-analysisof 14 trials, DHA supplementation

Table 1. Summary of Evidence for Effects of Consumption of Fish or Fish Oilon Cardiovascular Outcomes

OutcomeClinicalEffect

Strengthof Evidence Comment

CHD mortalityCHD deathSudden death

35% decrease 50% decrease

StrongStrong

Probable threshold of effectmost risk reduction occurs

with modest intake( 250 mg/d EPA DHA),with little additional benefitwith higher intakes2-4,6-17,45-51*

Ischemic stroke 30% decrease Moderate Strong evidence from prospectivecohort studies53,54; no RCTs

Nonfatal CHDNonfatal MI Modest benefit? Equivocal Possible benefits at very high intakes

( 2 g/d n-3 PUFAs)17,50

Progression ofatherosclerosis

Modest benefit? Equivocal Mixed results in cohort studies55

and RCTs56-58

Postangioplastyrestenosis

Modest benefit? Equivocal Possible benefits in a meta-analysisof RCTs59

Recurrent ventriculartachyarrhythmias

Modest benefit? Equivocal Mixed results in 3 RCTs60-62

Atrial fibrillation 30% decrease Limited Mixed results in 2 cohort studies63,64;benefit in 1 RCT65

Congestive heart failure 30% decrease Limited Benefit in 1 prospective cohort study66

Abbreviations: CHD, coronary heart disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid;MI, myocardial infraction; n-3 PUFA, n-3 polyunsaturated fatty acid; RCT, randomized clinical trial.

*See Figure 1.

Figure 3. Schema of Potential Dose Responses and Time Courses for Altering Clinical Eventsof Physiologic Effects of Fish or Fish Oil Intake

RelativeStrength

ofEffect

0 500 1500 250020001000

EPA + DHA Intake, mg/d

TYPICAL SUPPLEMENTAL

DOSES

Antiarrhythmia Weeks

Clinical Effect Time Course ToAlter Clinical Events

Triglyceride-Lowering Months to Years

Heart RateLowering Months

BPLowering Months to Years

Antithrombosis Weeks

TYPICAL DIETARY

DOSES

Therelativestrengthof effectis estimatedfrom effects of eicosapentaenoic acid (EPA)docosahexaenoic acid(DHA) on each risk factor and on the corresponding impact on cardiovascular risk. 70-72,79-84 For example, doseresponse for antiarrhythmic effects is initially steep with a subsequent plateau, and clinical benefits may occurwithin weeks, while dose response for triglyceride effects is more gradual and monotonic, and clinical benefits

may require years of intake. At typical Western levels of intake (eg, 750 mg/d EPADHA), the physiologiceffects most likely to account for clinical cardiovascular benefits include (1) modulation of myocardial sodiumand calcium ion channels, reducing susceptibility to ischemia-inducedarrhythmia;18,19 and(2) reduced left ven-tricular workload andimprovedmyocardial efficiencyas a resultof reduced heart rate, lower systemic vascularresistance, and improved diastolic filling.67-72,80 At higher levels of intake seen with fish oil supplementation orin Japanese populations49,50 (750 mg/d EPADHA), maximum antiarrythmic effects have been achievedand clinically relevant effects occur on levels of serum triglycerides79 and possibly, at very high doses, throm-bosis.75 Potentially important effects on endothelial,73 autonomic,74 and inflammatory43 responses are notshownbecause dose responsesand timecourses of such effects on clinical riskare notwell established.Effects arenotnecessarily exclusive: eg, antiarrythmic effects may be partly mediated by effects on blood pressure (BP) orheart rate.


1888 JAMA, October 18, 2006Vol 296, No. 15 (Reprinted) 2006 American Medical Association. All rights reserved.



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improved visual acuity in a dose-dependent manner.23 Results for cogni-tive testing are less consistent, possiblydue to differences in neurologic do-mains evaluated21,25,26; a quantitativepooled analysisof 8 trials estimated that

increasing maternal intake of DHA by100 mg/d increased child IQ by 0.13points (95% CI, 0.08 to 0.18).24 Mosttrialsevaluatedeffects of maternal DHAintake during nursing,rather than preg-nancy. In a trial among 341 pregnantwomen, treatmentwith cod liveroil fromweek 18 until 3 months postpartum in-creased DHA levelsin cord blood by 50%and raised mental processing scores, ameasure of intelligence, at age 4 years.97

This is consistent with observationalstudies showing positiveassociations be-tween maternal DHA levels or fish in-

takeduring pregnancy andbehavioral at-tention scores, visual recognitionmemory, and language comprehensionin infancy.98-100 Thus, while dose re-sponses and specific effects require fur-ther investigation, these studies to-gether indicate that maternal intake ofDHA is beneficial for early neurodevel-opment.

Risks of Mercury

Mercury is a reactive heavy metal emit-ted from natural sources (volcanoes)and human sources (coal-fired elec-tric power plants, gold mining, insti-tutional boilers, chlorine production,

and waste incineration).

101

From the at-mosphere, mercury cycles from rain-water into lakes and oceans, where itis converted by microbial activity intoorganicmethylmercury. Inorganic mer-cury is poorly absorbed following in-gestion, and elemental mercury doesnot readily cross tissue barriers. Incontrast, methylmercury is readily ab-sorbed and actively transported into tis-sues.27 Thus, methylmercury bioaccu-mulates in aquatic food chains and hasgreater potential toxicity than inor-ganic mercury.27,28,30 Concentrations of

methylmercury in aquatic species de-pend on levels of environmental con-tamination and on the predatory na-ture and lifespan of the species. Larger,longer-living predators (eg, sword-fish, shark) have higher tissue concen-trations, while smaller or shorter-lived species (eg, shellfish, salmon) havevery low concentrations (TABLE 2).122

Preparation methods have little im-pact on methylmercury content.27

Health effects of very high mercuryexposure following occupational or in-dustrial accidents are well docu-mented, including paresthesias, ataxia,

andsensory abnormalities in adults,anddelayed cognitive and neuromusculardevelopment following in utero expo-sure.27,131 Toxicity appears related tobinding of methylmercury to sulfhy-dryl groups of enzymes, ion channels,and receptors, resulting in inhibition ofantioxidant systems and production offree radicals and reactive oxygen spe-cies.27,29 Health effects of chronic low-level mercury exposureie, that seenwith fish consumptionare less wellestablished. The public is aware of thepotential harm from mercury in fish but

lacks clear understanding of who is atrisk or which seafood species containmercury.35,36We review the evidence forhealth effects below.

Methylmercury and

Neurodevelopment

Methylmercurycrosses the placenta, andfetal exposure correlates with maternal

Figure 4. Risk of Total Mortality Due to Intake of Fish or Fish Oil in Randomized Clinical Trials

5.01.00.2

Relative Risk (95% CI)

Source

Brouwer et al,62 2006

Brox et al,87 2001

Burr et al,3 1989

Burr et al,51 2003

Eritsland et al,88 1996

Gruppo Italiano,9 1999

Johansen et al,89 1999

Kaul et al,90 1992

Leaf et al,91 1994

Leaf et al,61 2005

Nilsen et al,92 2001

Raitt et al,60 2005

Sacks et al,56 1995

Singh et al,93 1997

von Schacky et al,57 1999

Overall

% Weight

3.9

0.3

18.7

24.4

2.9

26.0

0.7

0.3

0.4

4.6

4.6

2.3

0.3

9.9

0.6

100.0

Relative Risk

(95% CI)

0.57 (0.24-1.38)

0.17 (0.01-4.05)

0.71 (0.55-0.92)

1.15 (0.99-1.34)

1.23 (0.43-3.51)

0.86 (0.76-0.97)

0.33 (0.03-3.18)

0.28 (0.01-6.78)

0.20 (0.01-4.18)

1.09 (0.49-2.46)

1.00 (0.45-2.24)

0.40 (0.12-1.32)

0.32 (0.01-7.57)

0.56 (0.34-0.91)

0.50 (0.05-5.39)

0.83 (0.68-1.00)

The size of the shaded squares indicates each trials contribution (inverse-variance weight) to the pooled estimate (dotted line) and 95% confidence interval (CI; dia-mond), determined by random effects meta-analysis.37 Intake of fish or fish oil reduced total mortality by 17% (P=.046), with evidence for heterogeneity betweentrials (P=.04 for heterogeneity). If 2 trials with methodologic concerns 51,93 were excluded, the pooled relative risk was 0.83 (95% CI, 0.74-0.92; P.001) with littleevidence for heterogeneity (P=.75). A recently reported trial of fish oil among Japanese individuals17 was not included in the primary analysis due to very high fishintake in the reference group (estimated eicosapentaenoic acid docosahexaenoic acid intake, 900 mg/d) which would obviate mortality benefits of additional fish oilintake. When this trial was added to the secondary analysis, the pooled relative risk was 0.87 (95% CI, 0.76-0.99; P=.048; P=.29 for heterogeneity).





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exposure.132 Marked neurodevelop-mental abnormalities occur in childrenfollowing very high gestational expo-sure,27,131 such as from maternal con-sumption of highly contaminated fish(10-30 ppm mercury) from industri-

ally polluted Minimata Bay, Japan,in the1950s, or of contaminated grain in Iraqin 1971 (maternal intake, 710-5700ug/kg per day; 18-598 ppm mercury inmaternal hair). More typical methylmercury exposures are substantially

lower: among US women of childbear-ing age, median (10th-95th percen-tiles) levels of mercury in hair were 0.19(0.04-1.73) ppmoverall and 0.34 (0.09-2.75) ppmamongwomen consuming 3or more servings of fish per month.133

Table 2. Levels of n-3 Fatty Acids and Contaminants in Commonly Consumed Fish, Shellfish, and Other Foods*

EPA DHA,mg/serving

(Serving Size)

EPA DHA,mg/100 g

(3.5 oz)Selenium,

g/g (ppm)Mercury,

g/g (ppm)PCBs,

ng/g (ppb)Dioxins, TEQ

pg/g (ppt)

FDA action level33,102 NA NA NA 1.0 2000 None

Fish

Anchovy 1165 (2 oz) 2055 0.68 0.05 0.35 (1997-1998)103

Catfish, farmed 253 (5 oz) 177 0.15 0.05 50 (1997)104 0.53 (1995-1997)105

0.51 (1996)106

2.09 (1995-1996)107

1.65 (1995)108

Cod, Atlantic 284 (6.3 oz) 158 0.38 0.10 0.05 (1995-1997)105

0.15 (1995-1996)107

Fish burger, fast food 337 (2.2 oz) 546 0.17 0.05 8 (2001)109 0.01 (2001)110

0.11 (2001)109

Fish sticks, frozen 193 (3.2 oz) 214 0.17 0.05 0.04 (2001)110

Golden bass (tilefish), Gulf of Mexico 1358 (5.3 oz) 905 0.52 1.45

Golden bass (tilefish), Atlantic 1358 (5.3 oz) 905 0.52 0.14

Halibut 740 (5.6 oz) 465 0.47 0.25 1.00 (1995-1997)105

Herring, Atlantic 1712 (3 oz) 2014 0.47 0.05 0.97 (1995-1998)105

Mackerel, Atlantic 1059 (3.1 oz) 1203 0.52 0.05 0.87 (1997-1998)103

0.32 (1995-1998)105

Mackerel, King 618 (5.4 oz) 401 0.47 0.73

Mahimahi 221 (5.6 oz) 139 0.47 0.15

Pollock, Alaskan 281 (2.1 oz) 468 0.43

0.05 0.01 (1998)

105

0.24 (1998)111

Salmon, farmed 4504 (6 oz) 2648 0.41 0.05 21 (2001-2003)112 0.50 (2001-2003)112

15 (2002)113 0.87 (2002)114

40 (2002)115 0.45 (2002)115

26 (2001)110 0.33 (2001)110

25 (2001)116 0.50 (1997)105

51 (1999-2000)11738 (1999)116

Salmon, wild 1774 (6 oz) 1043 0.46 0.05 3 (2002)115 0.03 (2002)115

0.5 (2002)113 0.34 (2002)114

5 (2000)117

Sardines 556 (2 oz) 982 0.53 0.05 57 (2001-2003)112 0.44 (2001-2003)112

22 (2002)118 0.18 (2002)118

0.60 (1995)105

Shark 585 (3 oz) 689 0.34 0.99

Snapper 546 (6 oz) 321 0.49 0.19

Swordfish 868 (3.7 oz) 819 0.62 0.98

Trout 581 (2.2 oz) 935 0.15 0.07 11 (2002)113 0.56 (2002)113#0.32 (2002)114

0.74 (1998-2000)119

0.35 (1998)105

Tuna, light (skipjack) 228 (3 oz) 270 0.80 0.12 45 (2001)110 0.02 (1995-1998)105

Tuna, white (albacore) 733 (3 oz) 862 0.66 0.35 100 (2001-2003)112 0.23 (2001-2003)112

(continued)





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Table 2. Levels of n-3 Fatty Acids and Contaminants in Commonly Consumed Fish, Shellfish, and Other Foods* (cont)

EPA DHA,mg/serving

(Serving Size)

EPA DHA,mg/100 g

(3.5 oz)Selenium,

g/g (ppm)Mercury,

g/g (ppm)PCBs,

ng/g (ppb)Dioxins, TEQ

pg/g (ppt)

Shellfish

Clams 241 (3 oz) 284 0.64 0.05 3 (2001-2003)112 0.05 (2001-2003)112

2 (2002)118 0.05 (2002)1180.10 (1997-1998)103

Crab 351 (3 oz) 413 0.40 0.09 6 (2002)113 0.55 (2002)113#1.05 (1998)111

Lobster 71 (3 oz) 84 0.43 0.31 0.69 (1998)111

0.12 (1997-1998)103

Mussels 665 (3 oz) 782 0.90 0.15 7 (2001-2003)112 0.09 (2001-2003)112

0.8 (2002)113 0.11 (2002)113#2 (2002)118 0.07 (2002)118

0.39 (1998)105

0.45 (1995-1996)107

Oysters 585 (3 oz) 688 0.77 0.05 17 (2001-2003)112 0.46 (2001-2003)112

0.8 (2002)113 0.19 (2002)113#

Scallops 310 (3 oz) 365 0.28 0.05 0.16 (1998)111

Shrimp 267 (3 oz) 315 0.40 0.05 2 (2002)118 0.06 (2002)113#0.2 (2002)113 0.11 (2002)118

0.06 (2001)110

0.19 (1995-1997)105

0.08 (1995-1996)107

Other Foods

Beef 0 0 0.19 0 22 (2001)110 0.13 (2001)110

0.27 (1995)120

Bologna 0 0 0.14 0 0.16 (2001)110

0.29 (1995)120

Butter, regular 0 0 0.05 0 70 (2001)110 0.22 (2001)110

0.31 (1995-1996)107

0.66 (1995)120

Cheese 0 0 0.22 0 0.25 (2001)110

0.77 (1998)111

0.34 (1995)120

Chicken 0 0 0.23 0 32 (2001)110 0.02 (2001)110

0.20 (1995)120

Eggs 22 (1 egg) 43 0.23 0 19 (2001)110 0.05 (2001)110

0.52 (1998)111

0.31 (1995)120

Milk, whole 0 0 0.02 0 0.01 (2001)110

0.12 (1995-1996)107

0.13 (1995)120

Pork 0 0 0.34 0 18 (2001)110 0.10 (2001)110

0.23 (1995)120

Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FDA, US Food and Drug Administration; NA, not applicable; PCB, polychlorinated biphenyl; ppb, partsper billion; ppm, parts per million; ppt, parts per trillion; TEQ, toxic equivalence.

*Based on data from US Department of Agriculture (USDA),

121

Food and Drug Administration (FDA),110

Environmental Protection Agency,122

and other103-109,111-120,123-126

sources.These values may vary due to methodologic, geographic, temporal, and fish-to-fish differences. Levels of PCBs and dioxins may overestimate current levels because contami-nant levels in most foods, including fish species, are decreasing over time33,110,112,127,128 (eg, TEQs decreased by 33%-81% in meats 127 and 66%-77% in salmon and tuna fish 112

between 1995 and 2003); year of sampling is given in parenthesis.Based on USDA serving sizes: 2 oz anchovies or sardines; 1 fillet catfish, cod, mackerel, mahimahi, snapper, or trout; 12 fillet halibut, king mackerel, pollock, or golden bass;

6 oz salmon; 3 oz herring, shark, shellfish, or tuna; 1 piece (3.75 oz) swordfish. 121

The sum of dibenzodioxins (PCDDs) debenzofurans (PCDFs) (nondetects = 1/2 LOD when multiple estimates available).Due to numerous questions and uncertainties regarding scientific data on and analysis of dioxin risk.129

Forthe same specific species, there areminimal differences in nutritional or contaminant content of cannedvs fresh salmonor tuna. However, differentspeciesare typicallycannedvs sold fresh. For salmon, differences between species are small compared with differences between farmed and wild salmon. For tuna, canned light (skipjack) tuna and freshyellowfin/ahi tuna are more similar overall, while canned white (albacore) tuna and fresh bluefin tuna are more similar overall.

Measured including the fish skin; levels may be lower in the edible portion.130

#Includes dioxin-like PCBs.





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These exposure levels do not producesymptomatic neurodevelopmental defi-

cits, butseveralprospective studieshaveevaluatedwhether subclinicaleffects,de-tectable with specialized testing, mightoccur.98,100,134-140 Among children fromthe Faroe Islands,134, 135 New Zea-land,136,137 and Poland,138 higher gesta-tional exposure to mercury was associ-ated with lower scores on someneurologic tests(eg,finger tapping,nam-ing tests) but not others. In contrast,higher gestational exposure to mer-cury was associated with higher scoreson some neurologic tests among Sey-

chellois children.139,140

In a US cohort,gestational maternalfishintake wasposi-tively associated with, but mercury lev-els in hair were negatively associatedwith,visual recognition memory scoresin infancy,98 indicating possible oppos-ing effects of overall fish consumption(ie, providing DHA) and methylmer-cury exposure. In a British cohort, ges-tational mercury exposure was not as-sociated with, but maternal and infantfish intake was associated with, im-proved neurodevelopmental scores.100

Other studies did not detect consistentassociations between gestational expo-sure to mercury and neurologic testscores during childhood.141

Comparisons across studies are lim-ited by heterogeneity of study designs(prospective vs cross-sectional), mer-cury assessment methods, neurologictests used, timing of assessment (in-

fancy vs childhood), and statisticalmethods. Some analyses are also lim-

ited by multiple statistical testing (eg,30 neurologic variables) or incom-plete adjustment for other potential riskfactors. Randomized trials to test ef-fects of reducing low-level methylm-ercury exposure during gestation havenot been performed. Nevertheless,given associationswith some lower neu-rologic test scores in some studies, andclinical neurotoxicity of methylmer-cury following high-level accidental ex-posures, it is prudent to conclude thatsubclinical neurodevelopmental defi-

cits mayoccur at lower exposure levels.Based on this, the Environmental

Protection Agency determined a refer-ence dose, ie, the allowable upper limitof daily intake, for methylmercury of0.1 ug/kg per day (50 g/wk for a70-kg woman, calculated from thelower 95% confidence limit at whichgestational exposure to mercury mayproduce abnormal neurologic testscores, multiplied by a 10-fold uncer-tainty factor)132 and published a fo-cused advisory for women of childbear-

ing age, nursing mothers, and youngchildren.142 Theadvisory specifically ad-vises such individuals to avoid shark,swordfish, goldenbass, and king mack-erel (each containing 50 g meth-ylmercury per serving) (Table2); to eatup to 12 oz/wk (2 average meals) of avariety of fish and shellfish lower inmercury, including up to 6 oz/wk of al-

bacore tuna (30 g methylmercury perserving); and to consult local adviso-

ries for locally caught freshwater fish.This advisory was not intended for thegeneral population,because the impor-tance of this reference dose to healtheffects in adults was unclear.143We re-view the evidence for such effects be-low.

Health Effects of Methylmercury

in Adults

Cardiovascular Disease. Several stud-ies144-148 have evaluated the relation-ship between mercury exposure and in-

cidence of cardiovascular disease(FIGURE 5). The conflicting results pro-vide inconclusive evidence for cardio-vascular toxicity of mercury. Notably,in the 2 studies observing higher riskwith higher mercury levels, the neteffect of fish consumption wasstill ben-eficial: greater mercury exposure less-ened the benefit associated with con-sumption of fish or n-3 PUFAs but didnot increase overall risk.146,148,150 Thus,the principal question may not bewhether consumption of mercury-

containing fish increases cardiovascu-lar risk but whether consumption ofsuch fish would decrease risk even fur-ther if mercury were not present. Thiswould be most true for oily fish spe-cies containing higher amounts of n-3PUFAs (ie, most mercury-containingocean fish), compared with lean fresh-water fish. This is an important public

Figure 5. Multivariate Risk of Incident Coronary Heart Disease (CHD) With Higher Levels of Mercury Exposure

No. of Events

87

78

684

470

282

Study Design

Prospective

Prospective

Retrospective

Prospective

Prospective

Source

Ahlqwist et al,144 1999

Hallgren et al,145 2001

Guallar et al,146 2002

Yoshizawa et al,147 2002

Virtanen et al,148 2005

Overall

Relative Risk

(95% CI)

0.71 (0.4-1.26)

0.51 (0.21-1.24)

2.16 (1.09-4.29)

1.03 (0.65-1.65)

1.66 (1.2-2.29)

1.12 (0.71-1.75)

5.01.00.2

Relative Risk (95% CI)

Relative risk and 95% confidence intervals (CIs) are shown comparing the highest to the lowest quantile of mercury exposure after adjustment for other risk factors.In 2 studies in Sweden, higher mercury levels were associated with trends toward lower risk, 144,145 but findings may have been limited by relatively few numbers ofevents. In 2 larger European studies, positive associations between mercury levels and CHD risk were reported.146,148 A large US study observed no association,147 butmost participants were dentists, in whom mercury levels in part represented occupational exposure to inorganic mercury, 149 which may be less toxic than methylmer-cury in fish.27,28,30 The overall pooled relative risk (dotted line) and 95% CI (diamond), estimated using inverse-variancerandom-effects meta-analysis,37 was1.12 (95%CI, 0.71-1.75; P=.62), with significant heterogeneity between studies (P=.008).





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health issue, which requires balancingpotentially attenuated benefits of fishintake due to presence of mercury withthe costs and practicality of reducingmercury contamination in fish spe-cies. Nevertheless, this should not ob-

scure evidence for net cardiovascularbenefits of fish consumption, particu-larly fish richer in n-3 PUFAs.

NeurologicOutcomes.Veryhigh me-thylmercury exposure from accidents(eg,Minimata)27,151 or prolonged highin-takes of mercury-containingfish (eg, 1-2fish servings/d, including species highin mercury, for 10 years152) can pro-duce sensorimotor symptomsin adults,most commonly paresthesias, whichare often reversible when mercuryexposure is reduced. Whether lowerexposures produce neurologic abnor-

malities in adults is not clear. Cross-sectional studies have evaluatedassociations between mercury levelsin hair or blood and subclinical neuro-logic function in adults. Among Ama-zon basin and Quebec Cree individu-als,both positiveand inverseassociationswere seen between mercury levels andsomeneurologicmeasures,153-155 butfind-ings were limited by minimal adjust-ment for other risk factors andmultipletesting(typically20-30neurologictestsor participant subgroups). Among US

adults, mercury levels were associatedwith lower visual memory scores(P=.01) but better motor and manualdexterity scores (P=.02) among 20 dif-ferent outcomes evaluated.156 Amongelderly Swedish adults, no associationswere found between mercurylevels andcognitive function.157 Thus, it is unclearwhether low-levelmethylmercury affectssubclinical neurologic outcomes inadultsand, ifso,what quantitiesor dura-tions of exposure are necessary. Con-versely, a growing body of evidence

suggests that fish consumption mayfavorably affect clinical neurologic out-comes in adults, including ischemicstroke,53 cognitive decline and demen-tia,40 and depression and other neurop-sychiatric disorders.41,42

P o s s i b l e M e r c u r y - S e l e n i u mInteraction. Health effects of mercurymay partly result from selenoprotein in-

activation, which might be mitigated byadequate intake of selenium, an essen-tial dietary trace element.158-161 Sele-nium also may reduce tissue accumu-lation of mercury in fish1 6 2 an dhumans.163 Seafood species are rich di-

etary sources of selenium.

121

A protec-tive effect of selenium may partly ac-count for conflicting results of studiesof mercury exposure and neurodevel-opmental indices in children160 and ofmercury exposure and risk of CHD.164

A potential selenium-mercury interac-tion would have important publichealth implications, and additional in-vestigation is warranted.

Risks of PCBs and Dioxins

PCBs aresynthetic organochlorine com-pounds previously used in industrial

and commercial processes.34 Dioxinscommonly referring to dibenzodiox-ins and dibenzofuransare orga-nochlorine by-products of wasteincineration, paper bleaching, pesti-cide production, and production ofpolyvinyl chloride plastics.33 Manufac-ture and processing of PCBs was pro-hibited in 1977,34 and regulatory andindustry efforts have reduced dioxinemissions by more than 90% since1987.33 Nevertheless, these contami-nants persist for long periods in the en-

vironment, and thus while levels aresteadily declining,33,110,112,127,128 PCBs anddioxins continue to be present in lowconcentrations in many foods (Table2).

Cancer Risks. Animal experimentsand some evidence in humans indi-cate that PCBs and dioxins are carci-nogenic, possibly related to effects onthe aryl hydrocarbon receptor, a tran-scription factor affecting gene expres-sion.32,165 Multiple congeners (struc-tural variants) of PCBs and dioxinsexist. Potential toxicities of foods are

calculated using toxic equivalence(TEQ):thesumof each congeners levelin the food multiplied by that conge-ners toxic equivalency factor (stan-dardized against 2,3,7,8-tetrachlorod-ibenzo-p-dioxin). In the United States,PCBs comprise 28% and dioxins 72%of total TEQexposure.120 Amongadults,major dietary sources of PCBs and di-

oxins are beef, chicken, and pork (34%of total TEQ); dairy products (30%);vegetables (22%); fish and shellfish(9%); and eggs (5%).120 Dietary sourcesare similar for children.120

Although major sources of expo-

sure to PCBs and dioxins are meats,dairy products, and vegetables, consid-erable attention has been given to fishsources (Table 2). When PCBs and di-oxins were measured in farmed andwild salmon,115,166 levels were similar tothose in several other foods (Table 2).Farmed and wild salmon also con-tained substantial levels of n-3 PU-FAs: 4504 and 1774 mg of EPA andDHA per 6 oz, respectively.166 Cancerrisks and CHD benefits were evalu-atedin a quantitative risk-benefit analy-sis, assuming regular farmed or wild

salmon intake to provide 1000 mg/d ofEPA and DHA over a 70-year life-time.167,168 Per 100000 individuals,con-sumption of farmed vs wild salmonwould result in 24 vs 8 excess cancerdeaths, respectively, while consump-tion of either farmed or wild salmonwould result in 7125 fewer CHDdeaths.167 We further evaluated age-specific estimates, based on allocationof lifetime cancer risks167 (adjusted forcompeting risks) by age-specific can-cer mortality169 and 25% reduction in

age-specific CHD mortality.169

For allages evaluated (25-34 to 85 years),CHD benefits outweighed cancer risksby 100- to 370-fold for farmed salmonand by 300- to more than 1000-fold forwild salmon.

Notably, estimated CHD benefits arebased on prospective studies and ran-domized trials in humans (Figures 1and 2); estimated cancer risks includea 10-fold safety factor and are based onanimal-experimental data and limitedstudies in humansat high doses.168 Can-

cer estimates also assumed lifetimesalmon consumption to provide 1000mg/d of EPA and DHA (eg, four 6-ozservings of wild salmon every week for70 years). However, CHD mortality re-duction may be achieved with lower in-take:250 mg/d (Figures 1 and 2), orone6-oz wild salmon serving per week.At this intake, CHD benefits would be





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largely unchanged (7125 fewer CHDdeaths), while lifetime cancer riskwould decrease by 75% (6 and 2 es-timated deaths per 100 000 lifetimes forfarmed and wild salmon, respec-tively). Consistent with these very lowcancer risks, prospective studies in hu-mans have seen little evidence for ef-fects of fish intake on cancer risk.170

Other Risks. PCBs and dioxinsmay have noncancer risks in adults,

such as immune system or neuro-logic effects.32-34 Conversely, fish con-sumption may also have other ben-efits, possibly lowering risk of othercardiovascular outcomes (Table 1),dementia,40 neuropsychiatric disor-ders,41, 42 and inflammatory disor-ders.43,44 If present, such additionalpossible risks would have to exceedadditional possible benefits by morethan 100-fold to meaningfully alterthe present estimates of risks vs ben-efits. PCB content in fish can be

reduced 12% to 40% by trimmingbelly and back fat during filletingand by not consuming the skin.130

Also, contaminant levels are typicallymeasured in unprepared foods, andcooking may reduce PCB and dioxincontent.106

Prenatal (but not postnatal) expo-sure to PCBs and dioxins has been

associated with childhood neurode-velopmental deficits in several,171-177

though not all,178,179 studies. Becausemost exposure (90%) generallycomes from meat, dairy, and veg-etable sources,120,180 this concern isnot specific to fish consumption, par-ticularly since fish also containspotentially beneficial DHA. However,w o m e n c o n s u m i n g 1 o r m o r eservings/d of commercial freshwater

fish or consuming locally caughtfreshwater fish from highly contami-nated inland sources may be moregreatly exposed to PCBs and diox-ins180 and should consult regionaladvisories.

Related Considerations

Costs. We evaluated potential costs ofconsuming 250 mg/d of EPA andDHA from fish (FIGURE 6). The dailycost was as low as 9 cents, or 63cents/wk. For combinations of differ-

ent types of salmon; salmon andtuna; or salmon, tuna, anchovies,and sardines, the average cost was 37cents/d ($2.59/wk) or less. Actual(net) costs would be lower becauseintake of fish would replace intake ofother foods.

Supplements. Fish oil capsules con-tain 20% to 80% of EPA and DHA by

weight (200-800 mg/g185,186), little to nomercury,187 and variable levels of PCBs(0-450 ng/g,116,188) and dioxins (0.2-11TEQ pg/g114,189). Given small amountsof fish oil consumed (1-3 g/d), expo-sure to PCBs and dioxins from fish oil

intakeis low. Functionalfoods supple-mented with EPA and DHA (eg, dairyproducts, salad dressings, cereals) canalso provide reasonable intake to indi-viduals not consuming seafood.190 Com-pared with supplements, fishintake alsoprovides potentially beneficial protein,vitamin D, and selenium.121

Commercial Preparation. Commer-cially-preparedfried fishmeals from fastfood restaurants or supermarket fro-zen sections123,124 are often made us-ing white-meat fish (lower in n-3 PU-FAs)27,123 and prepared with partially

hydrogenated oils (containing transfats) or oils reused for multiple fryingc y c l e s ( i n t r o d u c i n g o x i d a t i v e/ deteriorative products191). Higher car-diovascular risk seen with fried fish in-take 1 5 , 5 4 , 6 3 , 6 6 m a y r e l a t e t o t h i sunfavorable balance of benefit vs harm(lower levels of EPA and DHA; higherlevels of trans fats/deteriorative prod-ucts) or to residual confounding fromother lifestyle factors. While further re-search is needed, it appearsunlikely thatmost commercially prepared fried fish

meals lower cardiovascular risk.n6:n3 Ratio. Ecologic studies and

limited animal-experimental data sug-gest that linoleic acid (18:2n-6) maycounteract potential benefitsof n-3 fattyacids,192,193 but this hypothesis has notbeen supported by clinical trials or pro-spective studiesin humans.16,194 A muchgreater changein thedietary ratio of n-6fatty acids to n-3 fatty acids can be prac-tically achieved by increasing intake ofn-3s (eg, going from no intake of oilyfish to 1 serving/wk) compared with

lowering intake of n-6s (which arewidely consumed in cooking oils, saladdressings, and prepared foods). Thus,for most populations, attention to rela-tive intakes of n-6 vs n-3 fatty acids maybe less important than simply increas-ing n-3 intake.

Aquaculture. Concerns exist aboutsustainability of some aquaculture and

Figure 6. Estimated Costs of Consuming the equivalent of 250 mg/d EPADHA From Fish

Fish Preparation

0 10 20 30 40

oz/wk

Ounces per Week to AchieveIntake of 250 mg/d EPA+ DHA

FilletFarmed Atlantic Salmon

CannedWild Pink Salmon

FilletWild King Salmon

FilletWild Silver SalmonCannedAlbacore Tuna

CannedLight Tuna

CannedAnchovy

CannedSardine

FrozenShrimp

FrozenScallops

FilletCatfish

FilletCod

0 0.50 1.00 1.50 2.00 2.50

Cost, $

Cost to Consume250 mg/d of EPA+ DHA

Costs were calculated for commonly consumed seafood species, based on retail prices (averaging the mostcommonly sold items in each of 6 US cities in the east, midwest, and south from a national online grocerystore181 or,for wildking andsilver salmon, from onlineretailers182-184) and on species-specific eicosapentaenoicacid (EPA)docosahexaenoic acid (DHA) content.121 Least expensive was canned pink salmon (9 cents/250mg of EPADHA); the average cost per 250 mg of EPADHA for these 12 types of seafood was 92 cents.

The corresponding ounces per week needed to achieve 250 mg/d of EPA

DHA is also shown.





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commercial fishing practices.195-197 Con-versely, aquaculture contributes toglobal fish production,198 and sustain-ability concerns are not unique toaquaculture or fishing but also exist foragricultural, forestry, freshwater, atmo-

spheric, and energy resources.

195,199,200

Some progress has been made, such aschanges in fish feeds to reduce depen-dence on fish meal or oil.195 Given theimportance of n-3 PUFAs for health,balance must be achieved between en-vironmental and economic concerns toallow sustainable, financially viableaquaculture and commercial fish-ing.195,196,199

Plant Sources. Alpha-linolenic acid(ALA) (18:3n-3) is an n-3fatty acid pre-sent in flaxseed, canola, soybeans, andwalnuts.121 In humans, ALA is con-

verted to EPA in small quantities (inwomen more than men); further con-version to DHA is very limited.201 Con-sumption of ALA (eg, 2-3 g/d) may re-duce cardiovascular risk202 or affectneurodevelopment, but benefitsare lessestablished compared with those forEPA and DHA.

Optimal Intakes

Optimal intake of n-3 PUFAs may varydepending on population and out-come of interest. In the general popu-

lation, 250 mg/d of EPA and DHA is areasonable target intaketo reduce CHDmortality. Because dietary n-3 PUFAspersist for weeks in tissue mem-branes,203 this can be converted to aweekly intake of1500-2000 mg.Thiscorresponds to one 6-oz serving/wk ofwild salmon or similar oily fish,or morefrequent intake of smaller or less n-3PUFArich servings (Table 2). For in-dividualswith CHD, 1000 mg/d of EPAand DHA is currently recommended toreduce CHD mortality.204,205 Our analy-

sis suggests that lower doses may be suf-ficient, but given this populationshigher risk and that most data are fromprimary prevention studies, a target in-take of 500 to 1000 mg/dconsistentwith the largest secondary preventiontrial to date9appears reasonable. Thiscould be approximated by one 6-ozserving/wk of fish richest in n-3 PUFAs

(eg, farmed salmon, anchovies, her-ring), more frequent consumption ofother fish (Table 2), or supplements.Optimal intake levels for other clini-cal outcomes are not well established.

The effects, if any, of low-level meth-

ylmercury exposure in adults arenot es-tablished; mercury may modestly re-duce the cardiovascular benefits of fishintake. One can minimize concerns bychoosing fish higher in n-3 PUFAs andlower in mercury or by simply consum-ing a variety of different seafood. Indi-viduals with high consumption(5serv-ings/wk) should limit intake of selectedspecies highest in mercury (Table 2).

DHAappears important forearly neu-rodevelopment. Womenwhoare or maybecome pregnant and nursing mothersshould avoid selected species (shark,

swordfish, golden bass, and king mack-erel; locally caught fish per local advi-sories) andlimit intakeof albacore tuna(6 oz/wk) to minimize methylmercuryexposure.31,142 However, emphasis mustalso be placed on adequate consump-tion12 oz/wkof other fish andshell-fish to provide reasonable amounts ofDHA31,142 andavoid further decreasesinalready low seafood intake amongwomen (74% of women of childbear-ing age and 85% of pregnant womenconsume6 oz/wk).206,207

Continued efforts to limit environ-mental contamination from organochlo-rine compounds are appropriate. How-ever, levels of PCBs and dioxins in fisharelow, similar to those in several otherfoods, and the magnitudes of possiblerisks in adults are greatly exceeded bybenefits of fish intake and should havelittle impact on individual decisions re-garding fish consumption (for locallycaught freshwater fish, women of child-bearing age should consult regional ad-visories).

CONCLUSIONS

Potential risks of fish intake must beconsidered in the context of potentialbenefits. Based on strength of evi-dence and potential magnitudes ofeffect, the benefits of modest fish con-sumption (1-2 servings/wk) outweighthe risks among adults and, excepting

a few selected fish species, amongwomen of childbearing age. Avoid-ance of modest fish consumption dueto confusion regarding risks and ben-efits could result in thousands of ex-cess CHD deaths annually and subop-

timal neurodevelopment in children.Author Contributions: Dr Mozaffarian had full ac-cess to all of the data in the study and takes respon-sibility for the integrity of the data and the accuracyof the data analysis.Study concept and design; acquisition of data; draft-ing of the manuscript; critical revision of the manu-script for important intellectualcontent:Mozaffarian,Rimm.Analysis and interpretation of data; statistical analy-sis; obtained funding: Mozaffarian.Administrative, technical, or material support; studysupervision: Rimm.Financial Disclosures: Dr Rimm reports that he hasreceived research funding from Merck, Pfizer, andGlaxoSmithKline, and that he has received paymentor honoraria for presentations about food and dietsfromthe US Environmental Protection Agency,the USFood andDrugAdministration,the Institute of Medi-

cine, the Culinary Institute of America, the Interna-tional Chefs Association, and academic conferencesfunded by Bunge and Unilever. Dr Mozaffarian re-ported no financial disclosures.Funding/Support: This study was supported by Na-tional Heart, Lung, and Blood Institute, National In-stitutes of Health grant K08-HL-075628.Role of the Sponsor: The National Heart, Lung, andBlood Institute had no role in the design and conductof thestudy; thecollection, management, analysis, andinterpretation of the data; or the preparation, re-view, or approval of the manuscript.Acknowledgment: We thank IngeborgBrouwer, PhD,Wageningen Centre for Food Sciences, Wagenin-gen, the Netherlands, for providing mortality resultsfrom the Study on Omega-3 Fatty Acids and Ven-tricular Arrythmia trial; Calle Bengtsson, MD, PhD,CeciliaBjorkelund, MD,PhD, LaurenLissner, PhD,andValter Sundh,BSc, TheSahlgrenska Academyat Gote-

borg University, Gothenburg, Sweden, for providingresults from their analysis of mercury and coronaryheart disease in Sweden; andWalter Willett, MD, DrPH,Meir Stampfer,MD, DrPH, andRuss Hauser, MD,ScD,Harvard School of Public Health, Boston, Mass, for in-sightful comments. None of those acknowledged re-ceived compensation for their contributions.

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