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U.S. Department of Health and Human Services

Animal & Veterinary

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Assessment of Risk: Pesticides

Roy Sjoblad, Ph.D.

(Slide.)

DR. SJOBLAD: Today I am going to try to give you some fundamental concepts of how risk assessment and risk management is applied at the Office of Pesticide Programs to pesticides and focus on gentamicin as a specific example of this process and how it normally might function in some of the unique issues that are brought to bear when gentamicin came in.

Please, microbiologists out there, ignore the capital A in amylovora. I know that just drives people crazy if you are a microbiologist. But I a non-microbiologist did the overhead. So forgive me.

I think that we all know that gentamicin is a glycoside antibiotic, very important. The World Health Organization considers it one of the 15 or so essential drugs. So I won't belabor that point.

In this short talk, we are going to be condensing a five-year process into a little over ten minutes. And so I am going to focus on some essential concepts. Basically, gentamicin came in as a conventional chemical pesticide. Okay And the proposal basically let's say for simplicity was in the aerial spray on apple orchards to control the gram negative Erwinia amylovora which is an enterobacteriaceae.

The use rate was a very low rate, about six grams AI per acre if I recall, and up to nine applications for a growing season. Pretty much if there is a -- whether a model would be used to determine whether Erwinia might be a problem and, therefore, the spraying schedule started as sort of a prophylactic treatment.

To understand the risk assessment and risk management process with gentamicin, I think we need to see a little bit about the structure and the function of the risk assessment and risk management branches in the Office. And I have listed six of the ten divisions are shown.

(Slide.)

Starting in the upper left, the Environmental Fate and Effects Division is a risk assessment division. They review data that the registrant submits on nontarget organisms, birds, fish, honey bee. They also look at data that are submitted, studies that are submitted on the fate of the particular active ingredient or pesticide in the environment.

Going down the Health Effects Division, they reviewed data that are submitted on mammalian toxicology. They also review product chemistry data, mainly the impurities in the formulation and also exposure data.

The Antimicrobials Division is a risk assessment and risk management division combined in one division. They basically perform the risk characterization of chemical disinfections with public health uses. And almost all of their products do not create that microbial resistance as would a standard clinical drug or veterinary drug wouldn't. And Dr. Nulent here who is doing the overheads can answer any questions you might have on that particular newly formed division.

I am in the Biopesticides and Pollution Prevention Division. It is a risk assessment and risk management division. We handle the microbial pesticides whether they are genetically engineered or not, --- plant pesticides and biochemical pesticides. And biochemical pesticides are naturally occurring materials that control the target pests by a nontoxic mode of action. And these would be things like phermones for instance.

Going down here, the Registration Division is a risk management division. And they -- all the information first comes into them for distribution to the relevant divisions for conventional chemical pesticides. Okay. If I could have the next overhead.

(Slide.)

I am just going to focus a little bit on the types of information that the Health Effects Division reviewers would be reviewing and summarizing and characterizing just as the previous speaker pretty much said. So that was -- you could say this data would be used, too, in a similar fashion.

Notice we have a battery of acute, sub-chronic studies, chronic studies in a number of different types of animal species. I don't want to focus -- I don't have time to focus on the specifics. I just want to get some concepts across, that the registrant is responsible for having these studies conducted. And they are done under GLP.

The registrants can request waivers based on scientific rationale. And the Agency will consider those requests for waivers. And, again, the data are used to identify hazard to applicators, workers, pregnant women, children. Dietary risks are evaluated in much the way that we heard previously.

Now, this is the type of information that was sent in for gentamicin, to support the registration of gentamicin in pome fruit orchards. Now, if I could go back to the previous overhead.

(Slide.)

The information when gentamicin came into the registration division, they take the data packages and distribute the relevant studies to the Health Effects Division or the Environmental Fate and Effects Division. And those go out for review. The reviewers then will summarize the data and the risk assessment will be done in the divisions. And then that is sent back to the Registration Division.

Gentamicin came in in about 1994, went into the Health Effects Division for review. And a toxicologist with microbiology experience, Roger Gardener, in the Health Effects Division was getting -- got this information under the secondary review process that goes on and had some questions about the potential for antibiotic resistance. He had not even considered this gentamicin as going through the standard process as a conventional chemical.

He happened to -- he just called me in the Biopesticides Division. And I got together with John Cowen and we went over and talked to Roger Gardener. And the next overhead will sort of summarize the events that occurred subsequent to this.

John Cowen and I and Roger basically drafted a memorandum advising HED on some of the uncertain nontraditional hazard identification issues related to gentamicin. Now, I think it should be clear that we had no established process to address these unique issues of potential risk from pesticidal use in the environment of clinically useful antibiotics.

(Slide.)

So we did consider that antibiotic resistance development and its maintenance and its transfer were potential hazard components of the risk assessment process. We concluded form all of the available information that the proposed aerial spray and orchards will select for gentamicin-resistant bacteria. And there was a strong possibility that the gentamicin resistance trait would be transferred to clinically important isolates. And the next overhead.

(Slide.)

This event could render gentamicin less effective or ineffective in the clinical setting. Now, right around this time, the Registration Division had gotten together -- had published in the Federal Register notice a proposed tolerance of 0.1 ppm of gentamicin in apples.

And this caused organizations like the American Society for Microbiology, Centers for Disease Control and the FDA Center for Drug Evaluation and Research to respond by showing their concerns about the potential for risk from use of gentamicin in the environment, okay, and the similar concerns as to the ones that the OPP staff generated were expressed by these agencies. And some of the key people are in the audience that were involved in some of these letters and also in an inter-agency panel that met, comprised of people from EPA, CDC, FDA and USDA.

So we concluded, too, with respect to, say, risk mitigation. That became the issue, you know, the subsequent issue. Can you mitigate this risk We believed that there was really no amount of reasonable study, either economically or scientifically, amenable type research, that the registrant could perform to provide reliable and predictive information to the EPA which would alleviate concerns for the risk of loss of gentamicin as an effective clinical antibiotic.

Okay. Under FIFRA, the Federal Insecticide, Fungicide and Rodenticide Act, it is really the responsibility of the pesticide registrant to provide the information and data to address identified hazards, even if they are beyond those that come under the traditional toxicology data setting.

I think to conclude, the process really thus far has been a useful model whereby there has been inter-agency communication which supported a risk management decision based on the best available scientific information and data. As a result of this process, the registrant has -- did withdraw its petition for the proposed use of gentamicin as a pesticide.

I want to say that the inter-agency panel when it did convene also was asked about exposure issues and mitigation of exposure by different types of processes that maybe an antibiotic like gentamicin could be used. And it was certainly not concluded that there could be some level of exposure which would not trigger these resistance development, maintenance and subsequent transfer. So that concludes my presentation.

(Applause.)

DR. STERNER: I can see our speaker are adhering to the threat that was made earlier at the start. We are moving along nicely. There is time for questions. Okay. Thank you very much.

Dr. Dick Whiting will go ahead and address our -- be our next speaker talking about microbiological risks. He has an active research program modeling the growth and survival of food-borne microbial pathogens. This ranges from formulating new mathematical models to composing a personal computer software program to make the models easily. Now, there is an oxymoron, isn't it, user-friendly software, and widely available.

The concept supporting the linkage of predictive modeling to a HACCP program through microbial risk assessment are currently being developed. Previous research has included the quality of microbiology of low salt meat products and the role of meat biochemistry in determining quality.

Dr. Whiting received his BS degree from the University of Wisconsin, his master's of science from the University of British Columbia and his Ph.D. from Oregon State University, all in food science. He conducted research with the USDA Agricultural Research Service from 1977 to 1998 and joined FDA CFSAN in 1998.

He has over 85 publications and 90 presentations, and was a member of the Microbial Food Safety Team that received the USDA Departmental Awards for developing pathogen models and the FSIS team that conducted the Salmonella enteritidis in eggs risk assessment.

Current activities include the Listeria monocytogenes risk assessment and the CODACS Committee on Food Hygiene. Dr. Whiting.