Can your fish oil cause you harm?

by Donna Chisholm / 28 September, 2016
Dramatic new research from Auckland scientists revealing the potential harm of “off” fish oil is the latest in a string of bad news stories causing a multi-million dollar headache for the former golden child of the supplements industry.
Photo/Getty Images
Photo/Getty Images

The rat babies are dying, quickly and in numbers. It is midwinter 2014, and for Auckland-based Liggins Institute scientist Dr Ben Albert, “it feels like the sky is falling” on his study into the effects of rancid fish oil on rat pregnancies.

His research earlier that year with then Liggins director Professor Wayne Cutfield had found more than half the 32 fish-oil brands sold in New Zealand were oxidised or “off” by the time consumers bought them. Now he is several months into a follow-up investigation, aimed at finding out what effect that oil might have if it’s used in pregnancy. With hundreds of pregnant women taking the supplements, ostensibly to boost their babies’ brain development, it is an important question to answer.

Hundreds of rat babies are being born, but the body count is rising fast – much too fast. Initially, it isn’t clear the deaths are occurring primarily in the group born to the rats fed oxidised fish oil, rather than those given good-quality oil or water. “I just thought my study was falling apart and we weren’t going to get any information,” says Albert.

In fact, the opposite was true. When he analysed his results several weeks later, Albert discovered that the mortality rate in the “off” fish-oil group of babies was eight to 13 times as high as the others.

“What made me feel a bit sick,” says Albert, “was thinking of the studies that have shown 20% of women take fish oil in pregnancy.”

Many women have been attracted to the supplements because of the science showing the omega-3 fatty acids they contain are important to support the growth and development of the infant brain – the World Health Organisation recommends the daily diet of pregnant and nursing women should include 300mg of omega-3s.

The study findings were a shock, Cutfield says. “We thought there could be an adverse outcome, but not this severe.”

The potentially large number of pregnant women using supplements is both comforting and disconcerting. Comforting in that it’s clear fish oil is unlikely to be killing human babies, but disconcerting because so little is known about the potential harms of oxidised oils.

“Using the principle of do no harm, we would not recommend pregnant women take fish oil [supplements] until we know one of two things,” says Cutfield. “One, whether the product sold is fresh or not, which currently we don’t know, or, two, we have a better understanding of the effect of degrees of oxidation, because it’s not going to be an all or nothing phenomenon.”

Dr Ben Albert: “We weren’t thinking of it as being a dramatic poison.” Photo/Ken Downie
Dr Ben Albert: “We weren’t thinking of it as being a dramatic poison.” Photo/Ken Downie

Trying to avoid ‘unnecessary angst’

But the ministries of Health and for Primary Industries won’t be making the same recommendation, saying the Liggins work doesn’t prove that the fish-oil supplements sold here could be harmful.

“We don’t believe this is showing a safety risk at all for pregnant women,” MPI food science and risk assessment manager Jenny Reid, speaking for both agencies, told the Listener. She says the study looked at rats, not humans, and the artificial oxidation levels the scientists applied to the fish oil were far in excess of the degradation that occurred in supplements naturally over time. The dosages of fish oil were also much higher than would be taken normally. “We believe this should not be extrapolated in any way to make reference to humans, and particularly to pregnant humans.”

Reid says the ministries are “trying to make sure it doesn’t generate unnecessary angst”, and although they don’t advocate pregnant women take fish-oil supplements, if they choose to do so, they won’t be risking their health.

MPI commissioned two Dunedin toxicologists to study the findings and concluded the levels of oxidation in the fish oils in the New Zealand market weren’t high enough to pose a risk to consumers. But Cutfield points out even that study commented there wasn’t enough human and animal data available to determine acceptable ­oxidisation levels.

Reid and the supplements industry also rounded on the Liggins’ testing methods, saying they weren’t validated or consistent with what was used in other fish-oil studies.

Albert rejects those claims. “She is dead wrong about this. We used the standard methods for measurement of oxidation as laid out in the European Pharmacopoeia.”

Professor Wayne Cutfield: “We thought there could be an adverse outcome, but not this severe.” Photo/Adrian Malloch
Professor Wayne Cutfield: “We thought there could be an adverse outcome, but not this severe.” Photo/Adrian Malloch

Another blow

The Liggins research, just published by the American Journal of Physiology, is nonetheless another blow to the fish-oil industry, which has seen booming sales begin to decline in response to international headlines questioning the supplements’ effectiveness in reducing cardiac deaths. Consider these damning headlines last year:

“Fish oil pills: A $1.2 billion industry built, so far, on empty promises” – Washington Post;

“Fading claims on fish oils” – New York Times; and

“Fish oil supplement research remains murky – Scientific American.

Italian researcher Dr Gianni Tognoni, lead author of one large trial involving 12,000 people, told the New York Times in 2015 that “the era of fish oil as medication could be considered over now”.

Dr Gianni Tognoni.
Dr Gianni Tognoni.

In the same article, University of Wisconsin cardiologist Dr James Stein noted that early fish-oil studies took place in an era when cardiovascular disease was treated very differently, but today’s standards of care are so good that “adding something as small as a fish-oil capsule doesn’t move the needle of difference”.

Fish-oil sales are worth more than $21 million a year in New Zealand, but in the year to June they dropped in value by 10%. Although total product sales were down more than 7%, Natural Products NZ executive director Alison Quesnel says the market is still strong and the decline is largely due to price cutting.

Internationally, however, the mood is less bullish. Adam Ismail, executive director of US-based GOED, the global fish-oil industry group, says the market in the US has fallen 10-15% from its peak in 2014 and acknowledges that reports questioning the supplements’ worth have had an impact. “There have been many decades of strong growth, so it’s concerning it would reverse course and that consumers are losing trust in omega-3s or forgetting about them or don’t remember the benefits,” he told the Listener from Utah. “The newspapers just want inflammatory headlines that sell, and the fact there’s a positive omega-3 story every other day doesn’t sell. Basically they’re saying, ‘Let’s throw the baby out with the bathwater.’”

Cutfield says he doesn’t want to throw the baby out, either. “We don’t want to give the message that fish oil will never be effective, but the evidence that it prevents heart attack and stroke is being disputed by more current evidence and we need to better understand what benefits it offers, not that it could never offer benefits.”

It’s possible, for example, that it may show some impact in regulating blood glucose – there is some overseas mouse-trial evidence that “good” fish oil in pregnancy may protect against diabetes and insulin resistance, but the Liggins Institute is still working on its own investigations.

GOED’s Adam Ismail.
GOED’s Adam Ismail.

‘Very dramatic’ effect on the rat babies

Cutfield says the “off” fish oil in Albert’s trial was very off indeed – two or three times the oxidation found in the worst of the products sold here – but the effect on the rat babies was “very dramatic”. There were also adverse outcomes in the mothers, whose insulin wasn’t working properly when their babies were weaned.

Of 187 babies born to mothers taking the oxidised fish-oil supplements, nearly 30% were dead by day two, compared with less than 3-4% of those born to more than 400 mothers given water or good fish oil.

When the babies in the “off” fish-oil group survived, some failed to gain weight, their fur was patchy, they tended to stagger and lurch when they walked and they had less fine motor control. The smallest of the survivors weighed just 13g when weaned at 21 days, while the average in the other two groups was 50g. The offspring of mothers fed the off oil were on average 30% smaller than those fed fresh fish oil.

Of course, as both the Liggins Institute and the government ministries point out, these are rats, not humans. But from a research point of view, unequivocal evidence of harm to humans may never be found – giving rancid fish oil to pregnant women in a clinical trial would be unethical.

Albert says the trial was originally designed to find out whether pure, high-quality fish oil might prevent obesity and diabetes in the rat offspring. “We thought the oxidised oil may not work and may have some negative effects, but we weren’t thinking of it as being a dramatic poison.”

Albert and Cutfield say they just don’t know what it is about the rancid oil that killed the rats. “We didn’t design our study to find out because we didn’t expect to see this,” says Albert. “We don’t know for sure if the [dead] rats were born alive or not because we don’t pick them up and look at them on day one, to avoid stressing the mother. We only know that many were dead by day two and more died by the end of the first week.”

Albert speculates it’s the result of oxidative stress and the consequent toxic effects. Oxidative stress is a mismatch between the production of free radicals and the body’s ability to counteract their damaging effects through antioxidants. In pregnancy, it’s associated with complications such as spontaneous abortion, pre-eclampsia and growth restriction.

Albert expects to be working on fish-oil studies for the next few years; the first follow-up will be to try to determine what level of oxidation causes harm. Ultimately, he wants to design a trial involving pregnant women to see whether high-quality fish oil has a positive effect on babies.

Dr Bill Harris.
Dr Bill Harris.

Ministry stops recommending fish oil

The Ministry of Health website still recommends fish-oil supplements for people with increased cardiovascular risk who don’t eat oily fish, but an endocrinologist and University of Auckland researcher, Associate Professor Andrew Grey, says that should be reviewed in light of recent meta-analyses that have shown little if any benefit.

The ministry says it’s updating and revising its cardiovascular and diabetes guidelines and now does not recommend fish-oil supplements. It says although omega-3 fatty acids are essential to a healthy diet, the best sources are oily fish, such as salmon, tuna, mackerel and sardines.

Grey says the declining sales figures for supplements suggest the message is finally getting through to consumers. In 2013, he and colleague Mark Bolland in a letter to the JAMA Internal Medicine journal asked why sales seemed to be steadily increasing despite “high-level evidence that the supplements lack efficacy across a range of health outcomes for which their use is advocated”. They surmised it was because of specialist bias, anecdotal evidence, low cost, ready availability, assumptions of safety and selective presentation of evidence by the supplements industry.

“We, the academics and doctors, are far too quick to embrace new treatments on the basis of low-quality evidence and fish oil is a good example of that.”

The popularity of fish-oil supplements exploded in the 1990s after research in the 1970s found that the Inuit population of Greenland, whose diet consisted almost entirely of fish, had very few heart problems. This work has since been discredited, with newer analyses finding the true rate of cardiovascular disease may have been vastly underestimated. More recent research has also found several DNA mutations in the population that mean they metabolise fish oil differently from the rest of us.

The fish-oil market took off in the US in 2002 when the American Heart Association said “omega-3 fatty acids have been shown in epidemiological and clinical trials to reduce the incidence of [cardiovascular disease]”.

Last October, one of the authors of that statement, Dr Bill Harris, a professor of medicine in South Dakota, told the Washington Post the current evidence was “unclear”, but “it all made a lot of sense at the time. There seemed to be a benefit and they were safe, so there was just no downside. Everything looked good, so why not do it?”

Professor Murray Skeaff: “You’re better changing your diet.”
Professor Murray Skeaff: “You’re better changing your diet.”

Evidence lacking

University of Otago professor of nutrition Murray Skeaff says although there is evidence that fish-oil supplements lower blood triglyceride concentrations – elevated levels of the lipids are associated with a higher risk of heart attacks – there’s still no proof that as a result of that, they reduce cardiac events.

“There are a lot of trials suggesting they have some effects on metabolism, and biochemical measures would suggest they should have influences that would reduce the burden of disease. But when you take them through to randomised controlled trials for secondary prevention [after a cardiac event], the evidence is that they are not effective.”

Most observational studies suggested people who eat fish tend to have lower risks of heart disease and he says it’s sen­sible dietary advice to substitute fish for some animal meats.

“People who eat fish tend to be healthier in many other respects. They tend to have lower saturated fat in their diets and to be more active.”

One meta-analysis the industry claims as providing proof of a reduction in cardiac deaths associated with supplements was published in 2012 by Greek researchers led by Evangelos Rizos. It found a 9% reduction in cardiac death, but when this was corrected for “multiple comparisons”, they found no effect.

Skeaff says if there is an effect, it’s small. “You’re better changing your diet to eat more fish.”

It’s a line now taken by many nutrition experts internationally. King’s College London professor of nutrition and dietetics Tom Sanders, who has researched the health benefits of fish and fish-oil supplements for more than 30 years, told the Daily Mail in 2012 that “fish-oil pills are more like snake oil”.

“I would always recommend eating fish twice a week instead and would leave off the pills altogether.”

He says many people take fish oil believing it will “ease aches and pains”, and although there is an element of truth to this, it takes 3g or more of fish-oil omega fatty acids to moderately reduce pain and inflammation in rheumatoid arthritis. “That’s about 15 times as much as you will find in a typical fish-oil capsule.”

Grey says there are still no good-quality randomised trials that show eating fish reduces the risk of heart attacks, either. Most famously, one study published in prestigious medical journal the Lancet in 1989 concluded fish did reduce further cardiovascular risk in men recovering from heart attacks, but when the trial was repeated in 2007 with a similar protocol, the researchers found an increase of oily fish in the diet was of no benefit.

Professor Tom Sanders.
Professor Tom Sanders.

Unrecognised downsides

The light-handed regulatory approach to supplements – unlike drugs, they don’t have to be proven to be safe and effective before being sold – is based mainly on the fact that apart from a few rare cases, they’ve seldom caused harm.

But another Liggins paper published last year by the American Journal of Clinical Nutrition suggests there are downsides that haven’t previously been recognised. The paper, which went largely unnoticed in the lay media, found overweight middle-aged men given a krill- and salmon-oil blend developed reduced sensitivity to insulin in just eight weeks. Insulin resistance exacerbates the risk of diabetes and heart disease. “The krill reduced the effect of insulin by about a third,” says Cutfield. “There is something in krill that has a bad effect and we don’t know what it is.”

Krill oil, a more expensive premium product, is among those that customers are “turning towards”, says Natural Products NZ’s Quesnel.

Cutfield says he’s been disappointed by the industry’s “shoot the messenger” approach to the Liggins findings about oxidation rates. “What we didn’t get from the industry was: ‘What do you think we need to do to have the purest product, because then we’ll market it and create a sales advantage?’ There wasn’t a single company that appeared to have that approach.”

The industry said it had done its own testing and did not find the same oxidation rates. At the time, Quesnel said international research “tended to find that most fish-oil products meet their active ingredient claims. It would appear that the findings are therefore related to an isolated incident rather than an industry-wide issue.”

But Cutfield says he wants the industry to acknowledge the issue and look into it, “rather than say our testing is not valid. The industry groups say they’ve done testing and they’re all fine, but independent groups find a different picture.”

Amber Yates, spokeswoman for Vitaco, which produces the Nutralife and Healtheries ranges of oils, says the company’s own testing and blind testing by GOED have found 100% compliance with oxidation and omega-3 content standards and therefore Vitaco has not changed its processing systems.

Albert and Cutfield have accused the industry of cherry-picking from academic studies by claiming that numerous meta-analyses of clinical trials of fish oil show it could reduce the risk of cardiac death.

Natural Products’ Alison Quesnel: the market is still strong and the decline is largely due to price cutting.
Natural Products’ Alison Quesnel: the market is still strong and the decline is largely due to price cutting.

In a 2012 paper, for example, Ismail claimed an analysis by Korean researchers that involved 20,000 patients in 14 trials found supplementation reduced the risk of coronary death by 9%. However, this study concluded: “Supplementation with omega-3 fatty acids did not reduce the risk of overall cardiovascular events, all-cause mortality, sudden cardiac death, myocardial infarction, congestive heart failure, or transient ischemic attack and stroke. There was a small reduction in cardiovascular death (9%), which disappeared when we excluded a study with major methodological problems.”

When questioned about his interpretation of the trial results, Ismail said the authors had originally included the paper, but pulled it out in a second analysis. “After they got the results, they said, ‘Okay, let’s pull out each individual study and see if one study drove the results.’” Other analyses had excluded the study from the start.

Ismail says most of the recent trials have involved people who already had heart attacks or strokes and were receiving drugs to lower blood pressure or cholesterol and thin their blood. “If you’re receiving the top standard of care for cardiovascular health, then fish oil might not make any additional benefit. But the question of whether ­omega-3s are valuable for heart health is completely different.”

He says some large clinical trials have found benefits in primary prevention, “but the evidence is still emerging”.

Cutfield says unlike the rigorous safety and efficacy trials on pharmaceuticals before registration, the scientific evidence is usually missing for dietary supplements. “Where are the studies that identify the compounds, establishing their biological effect, and how much you need to have an effect? And often that’s not there because it’s a very expensive exercise.”

When the institute released the results of its fish-oil tests in 2015, which showed how many were oxidised, it was criticised for refusing to reveal the brands that passed or failed. Eighteen months on, Cutfield defends that decision. He says batch-to-batch variability may have meant a brand that had an “off” product one day was fine the next and vice versa. “We didn’t test products from different batches, so while we showed that a customer is likely to buy fish oil that is oxidised, our results could create the wrong impression about individual products.”

Cutfield believes part of the problem for the fish-oil supplement industry is the time and distance between the oily fish catch and the shop shelf (see sidebar, page 20).

“Most New Zealanders think we’re surrounded by water, the fish is caught in the Hauraki Gulf, it’s in here by the afternoon and by 6pm it’s in capsules and on the shelves like the fish in the shop. I think they would be gobsmacked to find it can take up to three years.”

He says the industry can deal with the results in one of two ways. “One, they could say, ‘It appears we could have a problem, how do we fix it, because if we can fix it we could have a marketing advantage.’

“The other is ‘We’ve got bad news; how do you deal with bad news? You shoot the messenger.’ In other words, you attempt to invalidate or discredit or dismiss the research, and it’s otherwise ‘business as usual, we don’t have a problem’.”

Most of our fish oil comes from anchovies caught near Peru. Photo/Getty Images
Most of our fish oil comes from anchovies caught near Peru. Photo/Getty Images

It could be years old

Fish oil can take a long time to get onto the shop shelf.

We may be surrounded by ocean, but the fish oil on our supermarket and pharmacy shelves is sourced thousands of kilometres away, mostly from the anchovy fishery off the coast of Peru.

The catch spends up to six hours on board and up to 12 hours on land before being processed into fishmeal and crude fish oil. Because this involves heat, the oil is then rapidly cooled and an antioxidant is added.

Sometimes the oil is semi-refined before being shipped around the world. Shipping takes about a month, and refiners tend to buy 6-18 months’ supply of crude fish oil at a time to have enough to last until the next of two annual fishing seasons. The oil is stored in drums through which nitrogen is bubbled to displace residual oxygen before being shipped out again to be encapsulated.

It’s at this stage when there’s the greatest amount of oxidation, says GOED’s executive director, Adam Ismail. It does involve heat, but typically there is only a minor increase in oxygen. The bottles of capsules are flushed with nitrogen, and the gelatin surrounding the oil is another barrier to oxidation. It typically takes up to three months from encapsulation to the retail shelf, meaning in all, the oil in the capsules you buy could be more than two years old.

Amber Yates, a spokeswoman for Vitaco, which produces the Nutralife and Healtheries fish oils, says the company holds less than three months’ supply of finished product and is continually bringing in new supplies. She believes it typically takes around five or six months from catch to retail shelf in New Zealand, although “this is not necessarily the industry norm … it can take between six months and three years”.

Salmon, herrings, walnuts and flax seeds. Photo/Getty Images
Salmon, herrings, walnuts and flax seeds. Photo/Getty Images

Natural sources of omega-3

Omega-3 fish oils are more abundant in deep-sea oily fish such as wild salmon, mackerel, herrings, tuna, sardines and anchovies.

The two key omega-3 fatty acids are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The body can’t make omega-3 fatty acids, but some plants are rich in another type of omega-3, alpha-linolenic acid, which it can convert to DHA and EPA. Good sources of these are flax seeds, chia seeds, walnuts, pumpkin seeds and canola oil.

Deficiencies have been linked to a variety of health problems, including cardiovascular disease, some cancers, mood disorders, arthritis, and more. But that doesn’t mean taking high doses translates to better health and disease prevention.

– Source: Harvard Medical School

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