Methylmercury in Blood and Hair

Why Blood and Hair Concentrations Matter

The best evidence for the toxicity of methylmercury to humans comes from poisoning epidemics in Japan and Iraq.  However, in both those epidemics, the exact amount of methylmercury consumed by the people who were poisoned was unknown.  In Japan, by the time methylmercury was established as the cause of the disease, it was too late to figure out, at least on an individual basis, what the amount of methylmercury ingested was.  However, in Iraq measurements of mercury in blood and hair were taken in order to gauge how much people were exposed to afterward.  That can be done because mercury is slowly (months) removed from the blood, and mercury in hair can stay there for years.  Similarly, blood and or hair measurements have been used in epidemiology studies involving populations that consume large amounts of fish to gauge the extent of exposure of different individuals to methylmercury.

Predicting Blood MethylMercury Based On Dietary Exposure

Biomarkers are useful for characterizing the relationship between exposure and the toxic effects, but since most exposure to methylmercury is usually from fish, it leaves a question hanging:  What is the relationship between consuming fish on a regular basis and levels of methylmercury in blood and hair?  Since this is a very important issue, a study with four different controlled doses of methylmercury from fish in twenty human subjects over a ninety day period (Sherlock et al, 1984).  This study was conducted in the UK over thirty years ago, and because of current restrictions on the use of human subjects probably couldn’t be done today.  Since the change in blood concentrations relative appears to be linear (i.e. has the same proportion regardless of dose), the following analysis assumes linear in order to focus on two other issues, namely the impact of body weight and other unattributed sources of variation.

While recommended dosages of drugs are often prescribed without consideration of body weight, toxicologists usually presume that the internal dose (i.e the concentration in blood) will be directly proportion to body weight.  But contrary to either of those traditional approaches, Sherlock et al (1984) suggested that a correction factor of body weight to the one-third power is the most appropriate.  Since individual subject data were published in the paper, we can look for ourselves. 

The grey squares in the graph above show the uncorrected data from all 20 subjects.  There is clearly a correlation in the relationship between incremental methylmercury levels and body, indicating that some correction for body weight is necessary.  However, correcting the values by assuming proportionality (the black triangles) seems to overcorrect since it results in a trend going the other way.  The correction suggested by Sherlock et al, 1984 of body weight to the one-third power (black diamonds) does work well.  The best correction factor of all seems to of body weight to the power 0.44 (open squares); since the black regression line is completely flat, it corrects for the influence of body weight as well as possible.

However, there is still a considerable amount of variation that is not accounted for.  Using several alternative statistical distributions to describe the additional variation found with corrected values for a 70 kg person yields the following:

Predicting Hair MethylMercury Based On Blood Concentrations

Since most studies use hair as a biomarker, it is also necessary to relate hair methylmercury to dietary exposure from fish.  The a chronic study used n Sherlock et al (1984), also measured hair values (reported in Hislop et al. (1983), but only for the data from are the most relevant to a chronic exposure assessment.  However, hair values were only measured for five of the 20 subjects in the study, all of whom were male.  In addition, only the ranges for the hair-blood ratios are reported.  Other studies have more individual data points and are therefore potentially more useful at characterizing the full range of pharmacokinetic variability.  However, there are a number of other problems with these data. First, blood measurements fluctuate and are dependent on the time since the last fish meal, and as a result, measurements made at a single point in time may not accurately reflect long-term exposure.  Second, since inorganic mercury was not measured independently in hair, it is also possible that there is some contamination of hair from inorganic mercury – perhaps from environmental sources.  Third, errors in the chemical analysis are more likely to be substantial at lower concentrations in blood or hair (i.e. near the limit of detection), resulting in either unrealistically high or low ratios.  Regardless of the explanation, actual pharmacokinetic variation in the studies reporting single measurements of blood and hair is almost certainly narrower that the apparent distribution. 

The following figure shows summary data using a lognormal distribution to represent population variability with uncertainty distributions for the parameters.  The values were chosen to be centered on the values from Hislop, but to also encompass some of the variation from the other studies as well.

Software

Combining the results of the preceding analysis allows prediction of blood and hair levels, albeit with more than a little uncertainty.  Although the underlying functions are statistical descriptions of what happens in a population, they can also be used to predict what will happen in an individual if the population variability is treated as an additional uncertainty.  In that vein, a simple simulation for estimating personal concentrations for methylmercury in blood and hair is presented below.  It also includes a distribution intended to represent other exposures to methylmercury that is based on results from a survey of blood values in the U.S. (EPA, 2013).

The simulation is written in Microsoft Excel and has VBA macros, so macros need to be enabled and you are going to have to trust me as a source.  Sorry.

MeHg_Hair_and_Blood_Simulation.xls

References

Budtz-Jørgensen, E., Grandjean, P., Jorgensen, P.J., Weihe, P., Keiding, N. (2004).  Association between mercury concentrations in blood and hair in methylmercury-exposed subjects at different ages.  Environmental Research, 95, 385-393.

Centers for Disease Control and Prevention. (2005). National Center for Health Statistics, National Health and Nutrition Examination Survey, 2003-2004 data files.  There are more recent values, but they haven’t changed very much.

Hislop, J.S., Collier, T.R., White, G.F., Khathing, D.T., French, E. (1983).  The Use of Keratinised Tissues to Monitor the Detailed Exposure of Man to Methyl Mercury from Fish.  Chemical Toxicology and Clinical Chemistry of Metals, edited by Brown, S.S. and Savory, J.  Academic Press, New York, 145-148.

Sherlock, J., Hislop, D., Newton, G., Topping, G., Whittle, K. (1984).  Elevation of mercury in human blood from controlled ingestion of methylmercury in fish.  Human Toxicology 3:117-131.

U.S. Environmental Protection Agency (2013).  Trends in Blood Mercury Concentrations and Fish Consumption Among U.S. Women of Childbearing Age NHANES, 1999-2010.  Final Report July 2013 EPA-823-R-13-002.   

U.S. Food and Drug Administration (2014). Quantitative Assessment of the Net Effects on Fetal Neurodevelopment from Eating Commercial Fish (As Measured by IQ and also by Early Age Verbal Development in Children).   Additional technical details of the analyses described above can be found in Appendix C, section (a)(3). 

Software

A simple simulation for estimating personal concentrations for methylmercury in blood and hair.  It has VBA macros, so they need to be enabled and you are going to have to trust me as a source.  Sorry.

MeHg_Hair_and_Blood_Simulation.xls

Official Post Soundtrack

Supertramp (1974).  Bloody Well Right.  In: Crime of the Century, Track 2.

Post Notes

Thesis Post #55.  This is the first one with quantitative analysis, which is from the FDA fish risk benefit report.  I tried to make the explanations less technical, but I suppose that my success in that regard is pretty marginal.  l plan several on more, which will in the end develop into a personal risk assessment model that will deviate somewhat from what is in the report.  What is posted here just covers methylmercury pharmacokinetics.  A personal fish consumption module and dose-response functions for both mercury risks and fish benefits will be added later.  Lame live soundtrack is the best I could do.

Data Economics

In their recent seminal work, Longo and Drazo (2016) sketched out what might be called the trickle-down theory of data economics.  But, to really get off the ground, this fledging field needs some alternative theories.  Towards that end, a brief snapshot of the original theory and two alternatives are presented forthwith.

Haves vs Have-Nots

The Longo and Drazo theory posits that data is fundamentally the property of “front-line researchers” who created the data, and therefore, are the rightful owners of the data.   On the other hand, you have a new lower class of researchers that make no data whatsoever.  Many of these computer-toting “research parasites” probably never got a research grant in their life, never did an experiment, yet they somehow think they are entitled to data just because they don’t have any.  Slackers.

But, the data hosts can be magnanimous on occasion.  If it suits their interests, they may be willing to let the research parasites feed at their data trough by working “symbiotically”.  However, if the parasites are pushing a theory that doesn’t interest them, or even worse, runs counter to their own interpretation, forget about it.  And if the hosts are dead, well, the parasites are just going to have to go hungry.

Farmers vs Hunter-Gatherers

In this theory, the data makers are akin to farmers.  They toil in the fields near the Ivory Tower in which they live.   These farmers depend on the data they grow for sustenance.  But they often don’t consume the whole crop, and often leave much of it out in the field to rot. Out beyond the fields, there are a roaming class of hunter-gatherers.  These researchers are often living hand-to-mouth, just trying to get whatever data they can find that will help them solve the problem they happen to be working on that day.  Even though they do have their own data that they have gleaned from personal experience, as you may imagine, they often want to take it from the data farmers.  Scavengers from neighboring fiefdoms may also wander over to snatch data from the farmers too.

If the farmers really need the data for themselves, then of course they will object to having the data they created snatched from them.  On the other hand, if they have already gotten what they need, why not just let the gatherers have it?

Polluters vs Regulators

Industrialized countries are churning out data and releasing it into the intellectual environment at an ever increasing rate.  Unfortunately, instead of being released in pure form, the data are often contaminated with byproducts known as theories.  While these theories are often innocuous or even beneficial, many theories are deleterious to the mental health of anyone exposed to them.  The use of the log(dose) transform, for instance.

 

So, there obviously needs to be a public mechanism for mitigating the release of noxious theories into the environment.  The government could perhaps establish an academy to sort through epistemological disputes.  Oh wait, that already happened.  But, what if the academy itself is contaminated with bad theories?  Maybe there needs to be an open process for evaluating whether not the data really justify the theories they are issued with.  Hard to see how that can happen without making the data available unsullied.

Reference

Longo DL and Drazen JM (2016).  Data Sharing.  N Engl J Med 374:276-277

86 Billion Neurons, More or Less

A Few Basic Facts

A normal human brain has approximately 86 billion neurons, which is a lot even by mammalian standards.  What makes neurons special is that they are all interconnected by axons and synapses that let neurons send and receive signals to other neurons quickly.  Signals along the neuron and axon are transmitted by electrical impulses that are enabled by ion channels that briefly let charged ions cross the membrane of the cell.  Synapses connect axon terminals to dendrites in other neurons by molecules, called neurotransmitters, that are released from axon terminals and interact with receptors on connected dendrites.  Although the number of synapses each neuron has varies tremendously, the average number is estimated to be over a thousand, and the total number in the brain is estimated to be over 100 trillion (that’s 100,000,000,000,000). 

Not all neurons are the same in structure or function.  Some are closely associated with sensory systems (e.g. eyes and ears), some with motivational systems (e.g. thirst, hunger, fear, and sex), while still others are involved in controlling muscle activity, and then there are neurons that are connected with everything in general and nothing in particular.  While most neurons have short axons, some have long axons that connect to other neurons, muscles, and senses that are far away.  For example, there are neurons in the spinal cord that have axons that run the length of both arms and legs. 

Not all synapses are alike either.  Some are excitatory, meaning they stimulate the neurons they are attached to send a signal.  Others are inhibitory, meaning they act to prevent another neuron from sending a signal.  The neurotransmitters used at different synapses also vary.  While there are 10 different main neurotransmitters, there are many other minor transmitters as well.

Unlike most other cells in the body, most neurons are formed either before birth or shortly afterward.  It’s all downhill after that – the number of neurons decreases to at least some extent with age.  On the other hand, synapses some and go.  Although many synapses are formed when the brain is first developed, the formation of new synapses throughout life is what makes learning and memory possible.

Disrupting Brain Function

There are many ways different substances can alter or impair brain function.  The most common and well known mechanism is to either mimic or block the actions of neurotransmitters.  Caffeine acts that way, and so do many legal and illegal drugs.  Alcohol probably acts by generally impairing axonal transmission in all neurons.  Even though the actions of many neuroactive chemicals are temporary, an addiction can develop with prolonged use.  That happens because the brain adapts to having more or less of a particular transmitter, which means the brain will then function abnormally without the drug.  Short term effects on neurons can also be fatal.  For example, many pesticides act by preventing the deactivation of the neurotransmitter (acetylcholine) responsible for neuronal activation of muscles, including those responsible for breathing. 

But, some chemicals also have long term effects.  Alcohol can cause neuronal cell death, which is irreversible.  Other toxic chemicals can cause axons to degenerate, which may not grow back.  But, perhaps the worst thing a toxic chemical can do is to prevent the brain from developing in the first place.  That can happen when a substance either interferes with neuronal growth before or just after birth, or with the development of synapses before birth or later in life.  Methylmercury and lead are both examples of developmental neurotoxicants.  Methylmercury is thought to act primarily before birth, while lead exposure is thought to be most detrimental in young children.  However, the exact mechanism responsible for the effects of either lead or mercury is largely unknown.

Biochemical Neurotoxicology

There are bazillions of toxic molecules in the body.  Let’s take methylmercury for instance. The average methylmercury blood concentrations in the United States is about 1.3 µg/liter and the blood volume of a pregnant woman (and fetus) is about 4 liters.  So, an average pregnant women has about 5 µg of methylmercury in her blood.  Since the molecular weight of methylmercury is 231 there are Avogadros number (6.2 x 10²³) of methyl mercury molecules in 231 g, and 9.4 x 10¹² molecules in the blood of average an average pregnant woman in the U.S.   There’s also mercury in other tissues, including the brain, so let’s just round to an even bazillion.  The main point here is that there are a lot – even more than the number of neurons and about the same as the number synapses.

So, what happens if a molecule of methylmercury gets into the blood?  Usually, nothing.  It hangs around for a few months and then gets eliminated.  But some of it crosses the placenta and goes into the fetus.  But, even there nothing usually happens.  It may go back out again, or it may go into other tissues like muscle where as far as anyone knows it isn’t toxic.  But some it gets into the brain of the fetus.  But even there, most of it floats around inside or outside the neurons and does nothing.  But, on some rare occasions, the molecule of methylmercury will bind to something like an ion channel or a protein necessary for synaptic development, and sometimes that may keep the neuron or synapse from developing as it normally would.  But even that's not necessarily so bad.   One neuron or one synapse among billions or trillions isn’t going to be missed.  On the other hand, one molecule isn’t the problem.  A bazillion molecules may not really be much of an issue either.  But a bazillion here, a bazillion there, and pretty soon you are talking about a real problem where brain function is reduced to a noticeable extent.

Thresholds

Toxicologists don’t ever prove there is absolutely no effect – they can only show that if there is an effect it isn’t big enough to be detectable.  Yet, they often suggest that somehow they know that there is some dose of a toxic substance that does absolutely nothing, which is called a threshold (e.g. Barnes and Dourson, 1988).  There is no evidence for it, so the threshold theory is pretty much just a fairy tale that is often repeated because people like to hear it.  It is true that for a number of reasons, high level exposures can be much worse than low level exposures (e.g. cooperative binding, saturable metabolism), but that’s not really the same thing as a threshold: If several bazillion molecules have a noticeable effect, a bazillion or fewer probably do damage as well, only less.  In toxicology, less is better than more, so that’s good.  But if you would like zero, well you can’t have it.  Anyone who says otherwise is either lying or sadly mistaken.

In any case, the EPA has adopted the position that there is no threshold for the effects of lead.  In fact, that is given as a reason for not having a Reference Dose for lead (EPA, 2004).  On the other hand, the EPA supposes that there is a threshold for methylmercury and gives that as a reason for having a Reference Dose (EPA, 2001).  I think the EPA has it right for lead and wrong for methylmercury.  At least that’s the way my synapses have it sorted out.

References

Barnes DG and Dourson ML (1988).  Reference Dose (RfD): Description and Use in Health Risk Assessments.  Regul Pharmacol Toxicol 8:471-486.  Also at http://www.epa.gov/IRIS/rfd.htm

Environmental Protection Agency (2001).  Methylmercury (MeHg); CASRN 22967-92-6

Environmental Protection Agency (2004).  Lead and compounds (inorganic); CASRN 7439-92-1

Official Post Soundtrack

Pink Floyd (1973).  Brain Damage.  In: Dark Side of the Moon, Track 9.

Post Notes

Thesis Post #54.  This is a part of the semi-lay toxicology series that i began last spring but have done nothing with since.   I'm thinking a majority of by near future posts will be of this ilk, but we'll see. Besides providing a basic neuroscience overview, I am obviously taking on the threshold issue that still! has it hooks into the public and regulatory psyche.  Dumb, dumb, dumb.

Hydrogen Hydroxide

A Precautionary Tradition

The procedure used by the FDA to establish a level of exposure from pesticides and new food additives that will be considered safe by the U.S. government was developed over 60 years ago.  Even though it was and is somewhat arbitrary, this relatively simple standardized process is used to define “safety” without resorting to personal judgments.  This is achieved largely because many of the arbitrary judgments are standardized.  In particular, the statistical evaluation of the way uncertainties will be treated, and the use of standard safety or uncertainty factors to calculate a “safe” exposure determine the extent to which the evaluation will “err on the side of safety”.   There also may still be one more somewhat arbitrary decision, that will typically be made by an expert or group of experts, about what constitutes an adverse effect, but that’s it. 

A key characteristic of the Safety Assessment procedure is that it is designed to be precautionary.  In addition to erring on the side of safety, it was designed to be used for new chemicals that were previously not present in food.   But since it was first developed in the 50’s, procedures using safety factors have come to be used for many other regulatory applications as well.  In particular, when pesticide regulation was moved from the FDA to the EPA in the early 70’s, Safety Assessment was adopted by the EPA for more general purposes.  However, it didn’t always work very well.  In fact, sometimes it can be quite silly.

A Safe Level for Water

Hydrogen hydroxide, otherwise known as water, is a common ingredient in many foods and beverages.  Since it was commonly used before regulations were instituted for new food additives, it is clearly the sort of chemical that would be among the food ingredients that are Generally Recognized As Safe had, and therefore it is would not be regulated by a safety-factor based procedure - if anyone even considered it.  Nonetheless, for the sake of comparison, let us suppose hydrogen hydroxide was to be added to food or suddenly discovered for the first time.  What level of exposure would be considered to be safe?

There are very few formal studies of the toxicology of hydrogen hydroxide.   That is probably because water is not very toxic at all.  The median lethal dose (the LD₅₀) in rats has been determined to be greater than 90 g/kg body weight (Lewis, 2014), which means that even very large amounts of water (9% of total body weight) will kill some, but fewer than half of the rats consuming that amount . The reason drinking too much water can be lethal is well understood.  The kidney needs to maintain a proper balance of electrolytes, and it does so by eliminating water as needed.  But, if you drink too much at one time, it can’t keep up.   The hyponatremia that results can be fatal. 

Using the value of 90 g/kg body weight as a starting point, a safe exposure to water may be calculated with the application of standard safety factors:

• A factor of 10 because humans may be more sensitive than rats
• A factor of 10 to account for variability among humans
• A factor of 10 because a No Observed Effect Level was not identified

Dividing 90 g/kg bw by 1000 (10 x 10 x 10) yields a safe dose (e.g. an ADI or RfD) of 0.09 g/kg bw, or 90 mg/kg bw.  For an average adult (about 75 kg), that comes out to 7 g per serving, about half a tablespoon.  Any more than that wouldn’t be safe.  Yes, that’s silly – but why?

Thinking Again

Perhaps the first objection should be that applying the Safety Assessment procedure to water constitutes a use that it was not designed for; not unlike hitting a screw with a sledge hammer.  Perhaps Safety Assessment shouldn’t be used for chemicals that have always been in food.  You could even say that maybe it shouldn’t be used for chemicals that aren’t strictly optional.  You could still use Safety Assessment to identify already present chemicals that might be a problem, but not automatically conclude that being above the level identified as safe necessarily means that there is a significant problem.  Under those circumstances, perhaps the issue should be given more thought. 

So, if we are going to get serious about the safety of hydrogen hydroxide, what else needs to be considered?

• Perhaps we can whittle away at the safety factors a bit.  While there are no epidemiology studies concerned with the toxic effects of water, there are enough case reports to suggest that the susceptibility of humans is about the same as rats.  So, that should allow the animal-to-human factor to be dispensed with.  We could also find that there are many known instances of adults consuming one or even two liters at a time with no obvious adverse effects.  Those two adjustments will get our safe level of water to a far more practical 100-200 g (4 to 8 ounces) at a time.  But still, how terrible would it be to drink the whole can or bottle?
• Water is hard to avoid.  It’s in just about everything.  It’s even in the air you breathe!! You would have to carry around a calculator and a table of the percentages of water in everything you eat to make sure the safe level is not exceeded.   Is it worth it?
• Water is necessary.  Generally speaking, the risk of having too little hydrogen hydroxide is far greater than having too much.  It’s called dehydration.  So, instead of avoiding the consumption of 200 g in one sitting, on occasion it may be far riskier to not drink 500 g.  You can’t err on the side of safety when there are two sides to err upon.  Perhaps even one safety factor is too many.

Running the Marathon

For marathon runners, getting the right amount of hydrogen hydroxide is a serious matter.   One of the major obstacles to completing, or even surviving the race, is to get enough water to replenish the amount lost while running.  But, the amount needed varies, and it is also important not to drink too much.  At the very least, it will depend on the weight on the runner and the weather conditions.   Simple formulaic advice may be more dangerous than the more traditional approach of drinking when thirsty (Hendricks, 2011).  Therefore, any direction to the contrary deserves careful scrutiny. 

References

Ballantyne C (2007).  Strange but True: Drinking Too Much Water Can Kill.  Scientific American, June 21, 2007.

Hendricks N (2011).  Marathon runners who drink too much water are at risk of a deadly condition.  Washington Post, Oct 24, 2011.

Lewis RJ (2014).  Sax's Dangerous Properties of Industrial Materials, 12^th Ed.  John Wiley & Sons.

Official Post Soundtrack

Dire Straits (1978).  Down to the Waterline.  In: Dire Straits, Track 1.

Post Notes

Thesis Post #53.  Serves as an example of the misuse of the Safety Assessment Paradigm.

Why Should I?

Giving Advice

Governments, parents, and other authorities often give the subjects under their care advice about what to do, ostensibly for the betterment of their own welfare and that of others around them.  Two examples from the realm of traffic safety will serve to illustrate this phenomenon.  First, pedestrians are often told to look both ways before crossing the street.  Second, speed limits are usually in place on any given road that prohibit the speed at which vehicles may be driven.  The obvious difference between these two examples is that while compliance with the directive to pedestrians is voluntary (at least on the part of the government), the second is compulsory.  If you go above the speed limit, then the government is legally entitled to collect money from you, and perhaps take your license way.  There are no such consequences to pedestrians who only look one way instead of two.

Similar instances of government advice are to be found in food safety.  On the compulsory side of things, the government may legally limit which chemicals are added to food, and how much can be added when they are approved for use at all.  Food manufacturers who fail to comply with that government advice can have their products found to be “adulterated” and seized.  On the other hand, the government has far less authority to regulate chemicals that are aren’t deliberately added.  The practical reason for that is that it often isn’t possible to separate the chemical from the food.  As the main topic for this discussion, all fish contain methylmercury in varying amounts, which is known to be neurotoxic.  But, fish can also be an important source of many nutrients.   Consequently, many state public health departments and the federal government have issued advisories that direct expectant mothers to restrict how much and which fish they consume.  Compliance on the part of consumers is entirely voluntary.

Considering the Science

Generally speaking, authorities don’t tell people what to do without a reason.  For example, transportation departments keep statistics on accident rates, so they have a pretty good idea about how the frequency and severity of the accidents that occur will be with different speed limits.  They also have higher speed limits on roads used for commuting and intercity travel, and therefore set lower limits on streets that are likely to have pedestrians.  That doesn’t mean, of course, that everyone agrees with it.  People may disagree with the facts, or the decision given the facts.  But, if the advice is legally enforceable, it doesn’t really matter whether you agree or not; the penalty for failing to comply or not it the same.   On the other hand, if the advice is just a suggestion or guideline then you are free to disagree as you like.  For example, if you think looking in just one direction on a one-way street is sufficient, then you may do so.

On the topic at hand, a group of 30 senators recently addressed a letter to the Food and Drug administration concerning the advice to be given to pregnant women regarding fish consumption.  The concluding paragraph is as follows:

One of the FDA’s core responsibilities is ensuring that consumers have access to accurate, actionable information about the agency’s scientific findings.  Prior to issuing final advice, we strongly encourage you to consider the science underpinning the advice, and also the manner in which information is relayed to the consumer.  While we are eager for the advice to be finalized, it is critical that the final advice reflect the latest science and be presented to consumers clearly so they can make the best possible decisions about the nutritional value of seafood during pregnancy.

It seems that the senators are giving the FDA advice about what advice to give.  This advice may not be compulsory, but it is “strongly encouraged”.  So, what is it the FDA is being advised to do?  The most prominent directive is that this group of senators expects the agency to put consumers in a position to make their own decision.  That will obviously require the agency to in addition to (or perhaps instead of) telling pregnant women how much and what fish to eat, consumers should be informed of what is likely to happen if they eat less or more than the suggested amount.  This is especially important since the advice is voluntary; some women may prefer to eat less fish while others may prefer to eat more.

The other directive is that the FDA should “consider the science”.  This may sound trite, but it really isn’t.  For one thing, it means that in addition to giving the reasons underlying the advice, the agency can’t just make those reasons up.  It also means that the agency needs to take a public position on what the risks and benefits of eating fish are, and be willing to defend those assertions before the scientific community.  For example, the risk benefit analysis mentioned in the letter qualifies in that regard (disclaimer: I was a primary author of that report).  If the agency is currently unwilling to stake its reputation on that report (disclaimer: I don’t work there anymore) then they should be able to present the alternative that they are currently willing to defend. 

Because We Say So

Regardless of what scientific position the agency takes, it is clear that there also value judgments that go into deciding how much fish to eat.  For example, the risk-benefit analysis on the FDA web site describes neurobehavioral risks and benefits associated with the consumption of various species of fish, and estimates an optimal amount of fish consumption for each.  But, translating those results into how much fish should be consumed isn’t exactly straightforward.  There are judgments to be made about how important it is to be optimal.  Does 1 IQ point really matter?  How about one tenth of an IQ point?    How will the many uncertainties associated with estimated effects that are largely too small to measure accurately be resolved? 

The agency can, of course, place a value on small uncertain changes in IQ and other measures of behavioral performance themselves.  In fact, making value judgments on behalf of the public is what regulatory agencies are generally in the habit of doing.  Furthermore, that is exactly what many consumers want.  But, for fish consumption advice, that tactic almost certainly isn’t going to suit everyone; especially those people who are otherwise disposed to eat more or less fish than the prescribed amount.   In particular, wrapping all the science and value judgments into a single arbitrary number (e.g. the EPA Reference Dose) that defines “safety” without conveying any information about what anticipated health consequences are won’t put consumers, or anyone else for that matter, in a position to make their own decision.

References

Seafood Advice Letter to the FDA, Dec. 17, 2015

USFDA and USEPA (2014).  Fish: What Pregnant Women and Parents Should Know.  Draft Updated Advice by FDA and EPA / June 2014.

USFDA (2014).  Quantitative Assessment of the Net Effects on Fetal Neurodevelopment from Eating Commercial Fish (As Measured by IQ and also by Early Age Verbal Development in Children). 

Official Post Soundtrack

Smiths, The (1984).  What Difference Does It Make?  In: The Smiths, Track 8

Post Notes

Thesis Post #52.  Part of the fish advice saga, and the first that is based on current events. Unlike the the more historical posts on the same topic, this one is basically an editorial.

Plausible In Plausible Out

Computers are very logical and very obedient.  They will calculate the conclusion for whatever premises and assumptions they are given.  The one shortcoming, of course, is that the conclusions are never any more reliable than the premises.  Although using a computer to provide risk estimates often does hide shaky premises inside the proverbial black box, that doesn’t have to happen.  But, opening up the black box requires some effort on the part of both the programmers and the users.  In particular, there are three main things that need to happen:

Defining the Right Answer 

A risk assessment answers questions, and a good risk assessment will answer those questions well.    But, what does “well” mean here?

• True.  The obvious response to that question is the “true” answer.  But, if the scientifically true answer is, in fact, not known then that definition of “good” just isn’t practical.  A different answer is therefore often substituted: Garbage In, Garbage Out.
• Politically Correct.  If the true answer is not to be had, then risk assessment can be viewed as a set of standardized procedures and/or expectations.  Even though the answer isn’t really true, it is relatively simple to obtain, and that may on some occasions be sufficient to justify the use of default assumptions and the like.  Furthermore, as long as “politically correct” is not conflated with “true” then there is little or no harm done.  But, it seems to be inevitable that just that very thing happens: Acting upon a particular assumption leads people to believe it.  Gospel In, Gospel Out.  Reality then apparently become a product of political negotiation.  But people aren’t entitled to their own facts, not even in Washington.
• Honest.  Which leads to a third definition of “good”, which is “honest”.  While that sounds trite, it really isn’t.  “Honest” in this case doesn’t necessarily entail admitting to a moral failure.  Instead, it involves fessing up to uncertainty: An estimate with a narrower confidence interval isn’t really better unless that confidence is justified.  In fact, if moral judgment is an issue at all, it involves giving up the PC objective, where “good” really means “good enough”.  Perhaps the main difficulty with the honest uncertain answer is technical.  It is easy to say “I don’t know”, but that doesn’t answer the question and it may not be entirely honest either when something, but not everything, is known about the problem.  Therefore, the goal becomes to provide all plausible answers, rather than the single true answer.  Plausible In, Plausible Out can get complicated. 

The Other Probability

In the realm of words, different species of probability have been recognized and discussed for centuries.  Hume (1739) differentiated between the “probability of chance” from the “probability of causes”.  Even though Cohen (1977) called the other probability “nonpascalian” since Blaise Pascal is often credited with developing the mathematics associated with chance and statistics, Hacking (1975) credited Pascal with devising the probability tree, using it to give the theoretical probability for the existence of a Catholic god the same “epistemic standing” as an aleatory probability.  Yet, when risks become matters of degree, the other probability often disappears, and probability seemingly becomes synonymous with statistics.  The probability that inevitably gets left out when this happens is the theoretical sort.

However, there are many analysts who do find it useful to distinguish concepts of probability.  For, example Kaplan (1997) gave a keynote address at a Society of Risk Analysis meeting that gave outlined three concepts of probability.  One can be uncertain about variability, and one can entertain different theories that may account for a statistical reality.  Furthermore, the importance of model uncertainty in making many risk estimates is widely recognized.

The simpler part of solving the model uncertainty problem of is to employ a different formal representation, namely the probability tree, for a theoretical probability than for the continuous probability distribution that is typically used for statistical uncertainties.  But, the other thing that needs to happen is that the responsibility map for the division of professional labor needs to be redrawn.  When uncertainties arise, it is generally thought that the solution is to send in a statistician.  In fact, many statisticians do indeed themselves consider the Other Probability to be their responsibility, and as a result, have devised various and sundry Bayesian schemes intended to stuff the recalcitrant prior probabilities into an aleatory mold.  But, that’s not really what is needed.  Probability trees are the domain of multi-handed scientists (David, 1975), so if you want to assign a probability to a theory, ask them what to do.  Even if they can’t identify the correct theory, they should be able to say which are more likely and why: Maybe that’s a good way to find out who the better scientists really are.

Examining Assumptions

When assumptions are justified by tradition or regulatory policy, then the process of providing estimates do not provide an occasion for questioning the validity of the premises.  Not very scientific: Policy In, Policy Out.  Maybe the PC answer is within the realm of plausible interpretation, but who would know?  On the other hand, if an estimate is purported to be valid, then the premises are bound to be questioned, especially when there is health or money at stake.  That will call for a supporting argument. 

If one premise can be proven to the exclusion of all others, then Truth In Truth Out.  In some cases, a sensitivity analysis may demonstrate that the alternative assumptions yield about the same answer, thereby making the issue moot. But, with low-dose risk estimation, that doesn’t happen; the choice of model used to make the risk estimate matters a lot (NRC, 1994).  So, you have a probability tree.  Yet, which alternative theories make up the tree still matters, and scientific arguments still need to made for either including them or not.  An uncertainty analysis may make it easier to come up with a risk assessment that is scientifically credible, but that can only happen if the set of alternative assumptions can be defended as being at least plausible, and the full set encompasses the entire range of assumptions that are distinctly possible:  Probable In Probable Out.

Bayesian solutions to model uncertainty often allow probabilistic judgments regarding theories.  However, the general inclination is to relegate such judgements as “priors” that are subsequently modified based on the available data.  There are a couple of problems with that.  First, judging theories does not happen in a data vacuum; data has a lot to do with it.  Second, and perhaps more importantly, new data may to revision of the scientific judgments of alternative theories, or maybe even result in the introduction of a new theory entirely.  If that happens, Bayes theorem will have nothing to do with it.

References

Cohen, L.J. (1977).  The Probable and the Provable.  Oxford: Clarendon Press.

David, EE (1975).  OneArmed Scientists?  Science 176: 679

Hacking, I (1975).  The Great Decision.  In: The Emergence of Probability.  Cambridge University Press.

Hume. D. (1739). A Treatise of Human Nature, EC Mossner (ed.), London: Penguin Books. 

Kaplan, S (1997).  The Words of Risk Analysis.  Risk Anal 17:407-411.

Official Post Soundtrack

Clan of Xymox (1989).  Imagination.  In: Twist of Shadows, Track 8.

Post Notes

Thesis Post #51, Part of the solutions thread.

Dietary Supplements

No Approval Necessary

From a legal standpoint, there is a third class of food chemicals in the United States that are neither food additives nor contaminants.  Like food additives, these chemicals have an intentional use; when consumers buy them, they expect or hope that it will have some desirable consequence.   Yet, unlike food additives, they do not require FDA approval before they can be sold.  This is pretty much true by definition: If a manufacturer wants to get FDA approval, they can.  But if they decide that is too difficult or not possible, they can call it a Dietary Supplement and sell it anyway.

There are some restrictions.  If a manufacturers are going to sell a new supplement, they are supposed to notify the FDA and send in whatever information they have about the supplement.  The FDA may decide to object to the sale, or not.  In particular, dietary supplements are subject to the same legal standard as unintentional contaminants, so if the product is hazardous enough to meet the “may render injurious” standard, then the FDA can prevent sale of the product. 

Yet outside the commonality of “no FDA Approval”, the range of products that are sold as dietary supplements is tremendous, as are the reasons for NOT seeking FDA approval.  Some may be sold as supplements because the process for getting approval is too expensive for small companies, which is probably the most legitimate reason.  Some may be sold as supplements because they couldn’t meet the rather strict safety standards required for food additives.  The supplement route can also be used to avoid the approval process required for drugs.   And finally, products that really have no use at all can rather easily be sold as dietary supplements.

Nutritional Supplements

If a product is sold as a dietary supplement, nutrition is what most people have in mind.  There are nutrients like calcium, iron, and vitamins that some people don’t get enough of in their diet, and therefore they need supplements to meet their nutritional requirements.  So, supplement manufacturers put nutrients in pills, and sell then to consumers that may need them. Furthermore, the amount of a particular nutrient in a supplement generally follows recommendations made by the Federal government.  Since nutrients can also be toxic, dietary guidelines consider both how the amount of the nutrient is that is necessary and how much may be excessive  (Institute of Medicine, 2013).  That all sounds good, and it is. 

However, that doesn’t mean supplement purveyors won’t encourage consumers to buy supplements they don’t really need.  Free enterprise, yay.  For example, you can buy a manganese supplement.  Yes, manganese is an essential nutrient – that has been demonstrated in animal studies with controlled artificial diets.  However, there is no evidence that anyone has ever suffered from manganese deficiency.  On the other hand, there is evidence from human studies that indicate that manganese is neurotoxic with symptoms that closely resemble Parkinson’s disease.

Drugs

Many of the substances sold as dietary supplements are really drugs.  While nutrients are essential to normal structure and function, drugs are not.  Before the Dietary Supplement Health and Education Act of 1994, selling a drug as a supplement was illegal, but now it is not.   Like the drugs that are regulated by the FDA as drugs, the drugs sold as dietary supplements have a wide range of effects.  Many of them can be used to treat various diseases.  There are also many psychoactive substances sold as supplements that alter mood or behavioral performance.  The best known example is caffeine, which is also used as a food additive.

Perhaps the best example of the drug subcategory of dietary supplements is ephedra, a plant that contains ephedrine.   Ephedrine is a sympathomimetic compound that has many of the same pharmacological properties as adrenaline and other substances that occur naturally in the human body.  It is also very similar to many of the drugs (e.g. pseudoephedrine or Sudafed) found in over-the-counter cold medicines that can be obtained in the U.S. and elsewhere without a prescription.  In China, the herb is known as Ma Huang, which like many other products sold as supplements, has a long history of use in Chinese medicine.  It can indeed be a useful treatment for colds.  Ephedra has also been marketed as a stimulant (i.e. in “energy” supplements) and for weight loss.   It works for that too.  But, like many other drugs, it can have side effects, and an overdose can be lethal.  In fact, many people have died from ephedra overdoses.   As a result, and because the FDA can regulate supplements when there is demonstrable harm, ephedra has been banned.  However, you can still grow ephedra yourself, or order synthetic ephedrine from Canada and have it delivered to the United States.

The drugs sold as dietary supplements may or may not be better than drugs approved by the FDA as drugs.  Leaving that issue aside, there is another problem:  Products that are sold as natural remedies in other countries are sold as dietary supplements in the United States, which one might expect to lead some people to think of those products as foods, rather than medicine.  Since people don’t expect to OD on food, they are more likely to do so with a dietary supplement like ephedra.  That’s a problem.

Placebos

The third category of dietary supplements are comprised of substances that pretty much don’t do a damn thing.  You can put dirt in a capsule and sell it as a dietary supplement, and guess what, people do.  Giving people the hope of a cure can, in fact, be a cure; so maybe they are worth something.  A good exemplar here is Laetrile, otherwise known as amygdalin, which is found in bitter almonds, apricot pits, and cassava.  It is called a cyanogenic glycoside because it releases cyanide when ingested.   Even though there is no scientific evidence to support claims that laetrile or amygdalin can treat cancer or any other illness, it has been marketed and used as an anticancer agent.  It was especially prominent in the US during the 1970’s, when it came to called “Vitamin B17” even though it isn’t a vitamin at all.   Although the evidence of harm at recommended levels of use isn’t especially strong, the cyanogenic properties of amygdalin led to an FDA ban in 1971.

The biggest downside of placebos is that they may be used instead of a treatment that would work.  Nonetheless, the main thing the FDA does with regard to placebos is to regulate health claims; a supplement manufacturer cannot claim on the label or packaging that a supplement will produce a desirable health effect without getting FDA approval first.  However, supplement manufacturers can put whatever claim they want on the internet, and they do.  For example, they will tell you that Laetrile works: Google it for yourself.

Reference

Institute of Medicine (2013).  Dietary Reference Intakes Tables and Application.  National Academy of Science, Washington DC.

Official Post Soundtrack

Pere Ubu (1977).  Final Solution.  In: Terminal Tower, Track 3.

Post Note

Thesis Post #50.  Part of the Regulatory Toxicology series.