On May 24, the FDA asked six scientists to review the process the agency used to conclude that melamine and related compounds posed no health risk to people eating the meat of animals given contaminated feed. The document submitted for review was the Interim Melamine and Analogues Safety/Risk Assessment, in which the concept of the "dilution effect" was laid out.
Participating in the review process were:
Georges Benjamin, M.D.
Director, American Public Health Association
Samuel M. Cohen, M.D., Ph.D.
Professor and Chair, Pathology and Microbiology
Havlik-Wall Professor of Oncology
University of Nebraska Medical Center
Elaine M. Faustman, Ph.D.
Professor, University of Washington
School of Public Health and Community Medicine
Institute for Risk Analysis and Risk Communication
Lonnie King, D.V.M., M.P.A.
Director, National Center for Zoonotic, Vector-Borne and Enteric Diseases, CDC
Xavier Pi-Sunyer, M.D., M.P.H.
Director, Columbia University Obesity Research Center
St. Lukes Roosevelt Hospital Center
John Thomas, Ph.D., D.A.T.S., F.A.C.T
Professor, Indiana University School of Medicine
Department of Pharmacology and Toxicology
In a study released on June 7, the FDA concluded:
Overall, there was consensus from the peer reviewers that the conclusions of the S/RA were appropriate. In addition, recognizing the time-sensitive context in which the S/RA was developed and the time-sensitive need for the S/RA results, the peer reviewers concurred that the methodology, data, assumptions, and exposure scenarios used were appropriate.
Translation:
The FDA was working with limitations of what they knew and the timeframe in which they had to make an evaluation, and within those limitations, their conclusions, choices, and assumptions were appropriate. They are not saying they were correct, however.
After the jump, I'll include some of the actual comments made by the scientists. If you want to review the document itself, it's
here.
The reviewers made a number of comments and criticisms, none of which were attributed to a specific scientists. Among the key points:
There may be other data sources from studies of similar compounds pertinent for consideration; for example, one reviewer suggested that we consider studies that were conducted to evaluate the toxicity and metabolism of "triazine" pesticide compounds.
Translation:
Even though there was very little data about melamine and its analogues (cyanuric acid, ammeline, ammelide) to draw on, studies of other similar substances could have been used in this analysis. The reviewer specifically suggested looking at a type of pesticide, which has been studied.
Multiple sources of exposure should be considered, as there could be an additive effect. For example, one reviewer suggested that there may be exposure to melamine and its analogues from plastic products.
Translation:
Don't assume that the consumed food is the only possible exposure to melamine and its analogues.
Although one reviewer stated that "there is no evidence of bioaccumulation," other reviewers suggested that a scenario focused on possible chronic toxicity from longer duration exposure should be considered.
Translation:
Even if there is no evidence of bioaccumulation, the danger of exposure over a long period of time should be considered.
There should be some consideration of possible formation of other (more toxic) compounds such as might be created during heating.
Translation:
Just as we know that mixing melamine and cyanuric acid in a test tube causes the formation of a specific kind of crystal, FDA should consider that other processes, such as heating, might cause reactions that make these substances more toxic than they are on their own, or without being heated.
The report continued, saying "there was a consensus among the peer reviewers additional research is needed. " Additional areas where further research was recommended include:
Determine the concentration and crystallization of melamine compounds (MCs) in urine of different species, including possible co-crystallization (e.g., melamine and cyanuric acid) at lower concentrations due to hydrogen bonding effects between the MCs in enhancing crystallization and the effect of liquid and salt ingestion on the concentration of MCs in urine.
Translation:
We have seen melamine and cyanuric acid form crystals in urine in cats and dogs. We should also study if factors like ingested liquid and salt, as well as the way the compounds interact with each other, can influence that process.
Method development, such as more sensitive assays to detect low levels of MCs in tissues.
Translation:
Tests should be developed so we can find low levels of melamine, etc. in "tissues," ie, meat, organs, muscle, etc.
Toxicological studies with different species, including the examination of co-toxicity from exposures to multiple MCs to determine whether there are other additive or synergistic effects.
Translation:
We need studies on different species. We need to look at the effect of being exposed to many different substances similar to melamine, and find out if those combinations make things worse.
Studies to better understand melamine pharmacokinetics including the effects of dehydration, common medications (diuretics) and others that alter renal excretion.
Translation:
We need studies that take into account dehydration, including that caused by certain drugs such as diuretics, that might have an effect on kidney function.
Determine whether heating MCs forms new compounds in foods with greater toxicity than the parent compounds.
Translation:
Does heating melamine and its analogues make it combine into more toxic compounds?
Conduct longer term studies to determine potential toxic effects, including liver, reproductive or endocrine dysfunction.
Translation:
We need studies that cover a longer time period to see if these substances can harm other organs, such as the liver, or other systems, such as reproduction or the hormone system.
Determine whether biomarkers can be identified for predicting renal failure secondary to exposure to MCs.
Translation:
Are there other things we can look for, such as in bloodwork or some other symptom, that can alert us that kidney damage might be happening due to exposure to melamine etc.?
Comment:
The S/RA report clearly identifies the data and methodology used including the assumptions behind the methodology. Because of the general reported lack of clinical studies, a great deal of assumptions had to be made. While these may be found to be inexact in the future the authors make very conservative and reasonable assumptions to construct their methodology.
Translation:
The assumptions made by the FDA were reasonable. They may, however, still be wrong.
Comment:
Extent of contamination-One of the interpretation difficulties inherent in an incident such as this is the representativeness of the analyzed samples. Knowledge about the sampling strategy used to analyze contaminated media can assist the reader in understanding the extent of the problem however such information was missing from this report. Obviously concern for source identification is important and hence samples were only identified by letter or number however in order for this reviewer to understand how these samples were chosen for analysis (i.e. random or were these chosen for most suspected to be contaminated; where these samples from multiple supplier sources or all from one supplier and thus representative of downstream variation.). Such information is needed in order for this reviewer to support the "conservative" characterization of the risk assessment that is proposed on page 3.
Translation:
FDA says it was "conservative" in its assumptions, and thus the risk assessment errs on the side of caution. This reviewer is saying she or he was not given enough information to know if that's true, specifically about how the samples that were studied were chosen.
The next section is interesting. FDA asked the reviewers the following.
Question:
Are uncertainties in the S/RA identified and characterized?
Translation:
Did we tell you what we don't know for sure, and did we describe it well?
Most of the reviewers did not feel that FDA did a good job of this.
Comment 1:
Further uncertainties may need to be considered in the assessment. There should be a factor of 10 used based on interspecies variability (identified in the interim S/RA) but also an additional factor of 10 should be considered based on variations in human sensitivities and exposure differences. Combining these premises would produce a lower uncertainty factor which would also be consistent with most standard RA practices.
Translation:
There are things you didn't take into account. The fact that there are different species involved should have made you increase the risk by ten times, and you should also should increase it ten
more times because there are variations between individidual humans (sensitivity, exposure). It's standard scientific practice to combine these things and it would have reduced the uncertainty.
Comment 2. This is a lengthy comment, so I'll break it up. First part:
The report contains material in the appendices that does not appear to be fully addressed in main section of the report. For example, on page 9, Appendix 1, under the heading of Hazard and Toxicity both an LD50 and phrase "Exp. Carcinogen" is listed. The text should provide additional references and discussion of this listing. On page 10, Appendix 1 for Cyanuric acid, there are listings under biological use and importance that hint at other biological activities that could be related to its hazard potential for example, its use as a herbicide and information that in an ester form it may be an anticonvulsant or hypnotic.
Translation:
There are several things mentioned in the "footnotes" section that are not addressed in the risk assessment itself. Two examples are given, one about if a substance can cause cancer, and another about additional effects of cyanuric acid, including its use as an herbicide and that in one form, it might be used to sedate people or stop or prevent seizures.
The commentor goes on to ask:
Does FDA have any information on these properties or potential for these forms to be present under the current conditions? How potent are these materials? Is there information available from the Pesticides office of EPA (in RED documents) for cyanuric acid as an herbicide? This same page also lists this agent as an eye and skin irritant. Where did this information come from? At what exposures do these effects occur?
Translation:
This is basically just a recap of all the things FDA did not give enough information on, and specifically asked if the Environmental Protection Agency's Pesticides Office had been consulted, since it seems cyanuric acid can be, or is, used as a pesticide. Also, where is FDA getting the information in the footnotes about it being an eye and skin irritatant, and how much cyanuric acid needs to be in contact with eyes and skin for that to happen?
The commentor continues:
Other missing information includes lack of toxicological information that this reviewer would believe is present in the toxicological documents reviewed for this assessment. Since, references were not cited it is difficult for this reviewer to double-check if this is true. For example, on page 2 of the report many NOAELs were given from various animal studies however minimal to no information was provided about complete numbers and dose levels tested in each study. At a minimum such information is useful for understanding if the strength of support for the NOAEL being a true NOAEL rather than just the lowest dose tested. Such information could influence the size of the uncertainty factor used in the later stages of the risk assessment.
Translation:
First of all, "NOAELs" means "no observed adverse effect levels," and is common scientific language. This commentor is saying that FDA doesn't give references for the NOAELs it's giving from animal studies, so the reviewer couldn't check any of them to see if she or he agreed with the conclusion. This is important, because without knowing, for example, what dose was being tested at which no negative effects were observed, how can you know how that compares to this exposure?
FDA apparently concurred, because they responded, "A table of studies contributing to the S/RA will be added to the S/RA. This table will list dose levels and durations of studies."
FDA then asked:
Were scientific assumptions that are not strictly linked to the data explained and appropriate?
Three of the six reviewers did not feel they were. One did not respond.
Comment 1:
The S/RA as currently being considered is quite narrow in its interpretation and data consideration without the additional consideration of pertinent studies involving atrazine and similar chemical compounds.
Translation:
Without looking at the triazine pesticides, which are similar compounds, this assessment is too narrow and the conclusions aren't very valuable.
Comment 2:
The real challenge is extracting [extrapolating] rodent data to humans (I understand the studies are mostly in this species). However, since the event was precipitated by feline illness I would suggest you discuss what you do know about the pathophysiology of this exposure in cats and then transition to people.
Translation:
Pretty much all we know about is rodents. What about people and cats?
Comment 3:
No, for example the discussion on carcinogenic potential was not fully explained or sufficiently documented. One of the other reviewers of this assessment is Dr. Sam Cohen and his research on rodent tumors with saccharin is very relevant for this study however none of his mechanistic research is mentioned or summarized for relevance. Also, in order to support a non-genotoxic mechanism for cancer, the available mutation data and references would need to be cited. Some of this was listed in RTECS but not fully described or referenced in this document.
Translation:
FDA didn't do a good job of looking at the possibility this exposure could cause cancer. There is a study that might have been helpful with that, and its author is one of the reviewers of this document. Also, the citations the FDA was basing its conclusions on were not given, so can't be checked by the reviewers.
FDA asked:
Are the scenarios addressed representative and comprehensive, considering the public health risk evaluated?
Translation:
In order to determine the risk of something that has not happened and that hasn't been studied, we have to invent some of the details. Did we do a good job of that? Were the details we came up with good reflections of what really happens, and did they cover all possibilities?
Two of the six reviewers did not feel FDA did a good job with this. One of them said:
The three scenarios are quite useful but may not be completely representative or comprehensive. There may actually be worse case scenarios that should be considered in addressing potential public health risk. There might be a greater additive effect if multiple sources of exposure are considered. Another factor that should be considered is human consumption of pet food which does occur in some human populations. The final issue is the need to consider possible background exposures to melamine and its analogues likely through plastic products. One scenario should also focus on a longer duration of exposures and the potential outcome of chronicity.
Translation:
The details you came up with were useful, but may not have covered all of the things that could happen, and may also not have really reflected something that
would happen. There are "worst case scenarios" that weren't considered. There are problems of multiple ways someone could be exposed to these compounds. There is a possible issue of human consumption of pet foods. And also, what about longer periods of exposure, and the problems of ongoing exposure?
FDA then asked:
What are the prioritized research needs in relation to melamine and melamine related compounds, including the research that is needed to reduce the uncertainty associated with the S/RA?
Translation:
What do we need to research now, especially to make this risk assessment more accurate?
First comment:
There is clearly a need to develop and implement several research studies to help fill in knowledge gaps. These studies are listed in priority order from my perspective: 1. Identify complete structural activity to make sure that we are comparing the various compounds correctly; 2. Take contaminated food stuffs and identify exact chemical compounds that might result after heating the foods and then evaluate if the new compounds have greater toxicity; 3. Conduct longer term studies to determine other potential toxic effects including liver and reproductive or endocrine dysfunction; 4. Determine the possible additive and/or synergistic effect of melamine and its analogues that might result from co-exposures.
Translation:
There are lots of studies needed.
First, make sure we're even identifying these compounds correctly.
Second, see if heating makes a difference in toxicity.
Third, conduct longer term studies and make sure that systems and organs other than the kidneys are not affected, especially reproduction and hormone systems.
Four, study what happens when you combine these compounds ("additive" and "synergistic" effects).
Another commentor said:
The most obvious one is to look at other organs like gut, spleen, liver etc. for sub clinical accumulation or effects. Also, to better understand the effects of dehydration, common medications (diuretics and others that alter renal excretion of melamine pharmacokinetics.
Translation:
We need to look at other organs to see if there are problems that aren't causing symptoms, things that can only be seen if you look for them. Also, study how things like dehydration and common medications will change how these compounds affect the body.
Next comment:
This reviewer is supportive of the research needs listed in the document but feels that additional needs should include information on kinetics especially as this is directly related to the clearance issues. Determining whether these compounds breakdown internally or form esters internally would also be important to confirm. The importance of determining toxicity under co-exposure conditions is important. The report contains only a single line regarding reproductive and developmental toxicity and this would need to be verified or available data more thoroughly described. Much more exposure information about contaminate sources is needed.
Translation:
What happens to these compounds in the body? What happens when you're exposed to more than one compound, or there is more than one form of exposure? Two other areas where there is very little information and much more is needed are related to reproduction and possible harm to a developing fetus -- including causing the fetus to develop incorrectly. More information on where the sources used in the study were obtained is needed as well.
Next comment:
Information on the toxicity of melamine compounds and on the levels of melamine compounds in edible tissues would be very useful. It would be important to have more accurate analytical methods to detect low levels of melamine compounds in tissues. The crystals that have been found in kidneys should be characterized. Basic toxicological studies should be done in several species. The toxicity studies should include examination of co-toxicity when there is exposure to more than one than one melamine compound. Is there synergism or just additivity? Could biomarkers be identified that would raise an alert about renal failure secondary to melamine compounds?
Translation:
We need to know more about what happens when you eat the meat of animals who ingested melamine. We need to have better tests that can find low levels of melamine and related compounds in meat itself.
We should also have more information on what the crystals in the kidneys are like, in more than one species. Those studies need to also see what happens when an animal or human is exposed to more than one melamine compound -- is the effect just
additive, in other words, does it just "add up" to more, or is it
synergistic, in other words, does something happen when you combine them that doesn't happen to either one on their own? Last, can we figure out something we can test for that indicates a problem is about to happen before the kidneys fail?
Next comment:
Concentration and precipitation in urine of different species. Synergistic effects of the 4 chemicals in enhancing crystallization. More sensitive assay. Effect of liquid and salt ingestion of concentration of MC's in urine.
Translation:
We need to see what happens in different species. We need to figure out if any of the compounds together have effects they don't have on their own, such as forming crystals. We need a better test for levels of melamine etc. We need to figure out what effects drinking and salt consumption will have.
FDA just responded by thanking the reviewers for their suggestions.
I'm going to finish this on Thursday morning. Need another break.
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