The Safe or “Reference” Dose

See these related seafood lobby fables:
Fable: The EPA Reference Dose is 58 micrograms of mercury per liter of blood
Fable: The EPA Reference Dose is for lifetime exposure
Fable: The EPA Reference Dose includes a 10-fold “safety margin”

A general principle of environmental health is that risk increases with dose: At very low doses, the risk is also low, and as dose increases, so does risk, along a continuum. There is no “bright line” that divides safe from unsafe exposure, and individuals vary widely in terms of the dose required to cause harm.

Nevertheless, health agencies have found it useful to define a “safe” dose, to provide a reference point for comparison with consumers’ real-life exposure levels. In the United States, the “safe” (in quotes because safety is always relative) dose of methylmercury was defined in 1999 by the US EPA, and that definition was reviewed and endorsed in 2000 by an expert committee of the National Research Council/Institute of Medicine.

This safety standard is called the Reference Dose, abbreviated RfD. The reference dose is defined as the level of exposure that is reasonably certain to be without appreciable risk for a population exposed over a long period of time. For mercury, the population of concern to EPA was women of childbearing age (and their fetuses). No RfD was set for other population sub-groups, but the existing RfD can sensibly be applied to everyone, not just pregnant women. Stated simply, if pregnant women are most sensitive to harm, and the RfD is safe for them, then the RfD is probably safer still for other and presumably less sensitive groups.

The RfD expresses the amount of mercury that can be safely consumed per unit of body weight, each day. The RfD is 0.1 microgram of methylmercury per kilogram of body weight per day. (A microgram is one millionth of a gram.)

Because most Americans don’t eat fish every day, the EPA and FDA have addressed methylmercury exposure averaged over a week’s time. The “safe” dose of methylmercury for any given person is the RfD multiplied by the person’s body weight in kilograms, then by 7 (to convert daily dose to weekly dose.) For example, a 60-kilogram (132-pound) woman’s safe weekly dose is (0.1 microgram of methylmercury per kilogram of body weight per day) x (60 kilograms) x (7 days) = 42 micrograms of methylmercury.

This weekly reference dose can easily be compared with the amounts of methylmercury in different fish, to determine whether an individual’s exposure is within safe limits. Mercury levels in fish are expressed in parts per million; see FDA data on levels in different fish and shellfish. One part per million (ppm) is one microgram per gram. A standard serving of fish is six ounces, about 170 grams. The mercury dose in a serving of fish is therefore (mercury level in the fish, in ppm) x (170 grams). An individual’s weekly dose is the sum of the doses from different fish meals consumed over the course of a week.

A 132-pound woman has a reference dose of 42 micrograms; how much methylmercury does she get from six ounces of different seafood choices? Here are some examples:

Shrimp: 0.012 ppm x 170 grams = 2 micrograms
Salmon: 0.028 ppm x 170 grams = 5 micrograms
Flounder: 0.050 ppm x 170 grams = 9 micrograms
Light tuna: 0.118 ppm x 170 grams = 20 micrograms
Albacore tuna: 0.353 ppm x 170 grams = 60 micrograms
Swordfish: 0.976 pm x 170 grams =166 micrograms
Gulf of Mexico tilefish: 1.45 ppm x 170 grams = 246 micrograms

Obviously, the fish one chooses matters a great deal for mercury exposure, and it is not hard to exceed the “safe” dose, by a wide margin, by eating the “wrong” fish too often.

Individuals who want to calculate their own mercury exposure, based on the fish types and serving sizes they consume, can use the mercury data in Mercury Levels in Different Fish and Shellfish, or use the Mercury Calculator on the Got Mercury web site. To use the latter, a person needs to type in the variety of fish, the amount they plan to eat, and their body weight. The web site then calculates the mercury dose and expresses it as a fraction of the EPA RfD.

What happens if someone exceeds the reference dose? Usually, nothing obvious happens. Symptoms of toxic effects ordinarily don’t occur unless one exceeds the RfD by a fairly wide margin for an extended period. But as exposure increases above the RfD, risk increases, and the “reasonable certainty of no harm” becomes less certain. Since the effects of greatest concern are subtle disruptions in the brain, it is very difficult to be sure when harm is occurring, and prudent to try to minimize exposure.

The EPA has also calculated the level of mercury in blood that corresponds to dietary intake of mercury at the RfD. Using models of how ingested mercury is distributed in the body, EPA estimated that an average woman who consumed 0.1 micrograms of methylmercury per kilogram of body weight per day on average over a long period would have a level of 5.8 micrograms of mercury per liter in her blood. This level of blood mercury, called the EPA Reference Level, defines a long-term average level of mercury in blood that is reasonably certain to be without appreciable risk.

Just as consumers can compare their dietary mercury doses with the EPA RfD, people who get their blood mercury level tested (as part of their annual physical, perhaps—recommended for people who eat fish often) can compare their results with the EPA Reference Level of 5.8 micrograms of mercury per liter of blood.

The seafood lobby promotes several fables that can confuse people inclined to make such exposure comparisons. Here are the fables, and the facts on each:

Fable: The EPA Reference Dose is 58 micrograms per liter of blood.

Facts: This statement is wrong in two ways. First, the RfD is 0.1 micrograms of mercury per kilogram of body weight per day; it is an index of dietary mercury intake, not a level of mercury in blood. The latter is called the Reference Level. Second, the Reference Level in blood is 5.8 micrograms per liter, not 58 micrograms per liter. This error creates the impression that the EPA safe level is ten times higher than it actually is.

Sometimes the seafood lobby states outright that the “RfD” is 58 micrograms per liter, and sometimes they claim that it is 5.8 micrograms per deciliter. (Since a deciliter is one-tenth of a liter, this is the same as saying the limit is 58 micrograms per liter.) The use of the correct number (5.8 micrograms) with the wrong units (deciliters) is a more insidious error, and may be more likely to mislead those encountering it. It repeats the mistakes just described: It confuses the RfD, a measure of safe dietary intake, with the Reference Level, a measure of a safe mercury content in blood. And it overstates the actual Reference Level by a factor of 10.

Why would the seafood lobby consistently make such obviously incorrect statements on such an easily checked factual point? Sometimes they explain that they know the actual reference level is 5.8 micrograms per liter, but because “there is a 10-fold safety margin built into the RfD,” the actual “safe” level is 58 micrograms per liter. This claim is based on another major conceptual error. Frequently, however, they don’t explain, but simply assert flatly that the “safe” level as defined by the EPA is 58 micrograms per liter.

In early 2009, the seafood lobby tried briefly to inflate the true Reference Level by 100-fold. In challenging a reporter who had eaten a can of albacore tuna a day for 20 days and seen her blood mercury level rise from 4 to 17 micrograms per liter, to suggest that this increase was trivial, the National Fisheries Institute boldly asserted that “The EPA has deemed 580 micrograms per liter [emphasis added] to be a level of mercury in blood that approaches risk.” When this claim was exposed by another reporter, NFI did a quick about-face, claiming it had made a “decimal point error” in converting micrograms per deciliter to micrograms per liter. They then backtracked to their longstanding false claim that the safe level is 58 micrograms per liter.

Fable: The EPA Reference Dose is for lifetime exposure.

Facts: The seafood lobby uses this fable to suggest that consumers don’t need to be concerned about short-term high exposure to methylmercury. They assert that, as long as one’s average lifetime exposure is below 10 times the RfD (which the lobby likes to claim is the safe level), there is no risk associated with occasional high exposures. This claim is fundamentally wrong on scientific grounds, and potentially dangerous if consumers believe it.

The RfD is in fact based on “chronic” exposure, that is, exposure averaged over a fairly lengthy period. For many people, under most conditions, a single meal of high-mercury fish, now and then, is unlikely to be harmful. But based on both what is well known scientifically and what is not known, the “long term” is definitely not a lifetime, and there are reasons for caution, even about single high-mercury meals, for a pregnant woman.

The health risk of greatest concern is damage to the developing brains of babies in the womb and in young children. The period the Reference Dose applies to is therefore a pregnancy and the first few years of life. A woman’s mercury intake before she becomes pregnant and while she is breast-feeding can also affect the exposure of her fetus and newborn baby, so the critical time frame may extend to two years or so. But mercury exposure matters most in the womb and the first few years of life, when the brain is growing and developing most rapidly. Since the child is the vulnerable party, the woman’s lifetime exposure is largely beside the point.

Environmental health experts also have long recognized that exposure does not need to be constantly high to cause damage. There is substantial experimental evidence (in animals) showing that occasional short-term peaks of exposure, such as might occur from a single meal, or a few meals over the course of a week or two, of high-mercury fish, can significantly damage fetal development, if they occur during critical developmental stages. In other words, both the amount of exposure and the timing of exposure are crucial to whether damage occurs. Although there is much still unknown about the effects of short-term spikes of methylmercury exposure during human pregnancies, what is known on this topic provides an ample basis for advising women to avoid mercury exposure as much as possible before, during (and after, if they are breast-feeding) pregnancy.

Fable: The EPA Reference Dose includes a 10-fold “safety margin.”

Facts: This slightly different approach to spinning an extra factor of 10 into the EPA’s definition of safe exposure levels is based on a serious conceptual error.

When the EPA set the Reference Dose, it began with a level of mercury in blood that had a statistically significant adverse effect on children’s cognitive development, in the best-designed epidemiological study. That “benchmark” blood level was 58 micrograms per liter. So, from the outset, 58 micrograms per liter was known to be a harmful level, not a no-effect level, a “level that approaches risk” or any other industry distortion. EPA then applied a 10-fold “uncertainty factor” to calculate the Reference Level of 5.8 micrograms of mercury per liter of blood, from which it then derived the Reference Dose of 0.1 micrograms of methylmercury in the diet per kilogram of body weight per day.

An “uncertainty factor” is not a “safety margin.” An uncertainty factor is applied to account for unavoidable scientific uncertainties. One major source of uncertainty in this case is the lack of any obvious “threshold” below which exposure to methylmercury has no adverse effects; in fact, the level of mercury in blood at which no adverse effects occur has not been determined. A second source of uncertainty is the well known variability of individuals’ sensitivity to toxic effects.

People vary in their response to mercury in the diet in two critical ways: First, the blood level that results from a given dose in the diet varies, and second, individual sensitivity to the toxic effects of mercury at any given blood level varies.

An uncertainty factor in a safety standard seeks to account for known human variability, so that sensitive individuals, as well as the average person, are adequately protected. In this case, EPA used empirical data to model the relationship between dietary mercury intake and blood mercury; that evidence showed at least three-fold variation in dietary doses associated with an average blood mercury level of 58 micrograms per liter. EPA then applied an additional factor of three to take into account likely (but unmeasurable) variation among individuals in sensitivity to toxic effects. The combined effect of applying two factors of 3 was a reduction of the RfD by a factor of 9, rounded off to 10 for simplicity’s sake.

Thus, there is no “10-fold safety margin.” Starting with a blood mercury level that had clear, measurable adverse effects, 58 micrograms per liter, EPA divided it by 3, because some people develop a blood level of 58 micrograms per liter from 1/3 of the dietary intake that produces this blood level in the average person. EPA then divided by 3 again, because some people are likely to experience adverse effects at blood mercury levels 1/3 as high as those that affect the average person. By including both of these variables, EPA tried to set a reference dose that would be “safe” for people at the sensitive end of the normal human distribution, not just for average individuals. One size does not fit all, and whatever “safety margin” may be built into the reference dose is sure to be different for different people. Some experts in mercury toxicity believe that an RfD at least 50 percent lower would be fully justified by the available evidence.

In fact, two studies published in 2008, one in New York City and one in Boston, have measured adverse effects of low-level mercury exposure on the developing brains of babies whose mothers ate fish just twice a week or less, and whose blood mercury levels—although significantly higher than average—were close to or even below the EPA Reference Level. This evidence strongly suggests that even ordinary exposure to mercury from fish poses a risk to the developing brain, and that there is no actual margin of safety at all built into the RfD.

The bottom line: The RfD, the current definition of safe exposure, was based on evidence that was available when it was set, in 1999. While the RfD defines “reasonable certainty of no harm,” some uncertainty still remains within that “reasonable certainty.” The RfD protects different individuals to different degrees, and for some, the margin between the RfD and a potentially harmful exposure is undoubtedly quite narrow. As future research provides better data, the RfD is likely to be revised.