ࡱ> BDAc >jbjbSS P11:] ,  :@T@ K Anatomy of a Risk Assessment Under the FQPA: the Azinphosmethyl (Guthion) Case Allan Felsot Washington State University Before any pesticide is registered, the EPA must approve a tolerance for each crop use; tolerance being the maximum amount of chemical residue legally permitted on or in the crop. The pesticide manufacturer or registrant proposes the tolerance based on the magnitude of residues at harvest. Before the Food Quality Protection Act (FQPA), the EPA validated a registrants proposed tolerance guided by the mandate to protect the public health. Residues in food were the sole consideration for determining public exposure to pesticides. The EPA could also balance the benefits of a specific pesticide use against any health risks. The FQPA redefined a valid tolerance as one that would be safe. A safe tolerance ensures a reasonable certainty that no harm will result from aggregate exposure. Aggregate exposure refers to exposure from residues in drinking water and residences in addition to food. The EPA has determined that approximately 80% of pesticide residue exposures come from food, 10% from drinking water, and 10% from residential use, which includes interior and exterior pest control applications. The Road to Safety Being reasonably certain that no harm will come from legally permitted pesticide residues is an expensive proposition. Manufacturers usually cite figures hovering around 70 million dollars to successfully register a pesticide. A significant portion of this money funds the experimental studies that provide the data EPA needs to validate a tolerance. The whole exercise is called a risk assessment. Risk assessments for protection of human health have two components: toxicology and environmental chemistry. The toxicology portion involves experiments, usually with rodents but sometimes with dogs, that define the relationship between dosage of the pesticide and measurable adverse effects. The environmental chemistry provides information about potential exposures. Analytical chemistry is employed to quantitate residues in food, water, air, and soil. The risk of harmful effects (or no effects) is a function of the pesticide dose (associated with effects) and the magnitude of exposure. Toxicological Studies Determine the Relationship Between Dose and Response EPA requires over twenty different toxicology studies to determine the highest dose that causes no adverse effect (i.e., the No Observable Effect Level, NOEL). One reason that so many toxicological studies are required is that the NOEL may vary according to the route of exposure (i.e., dermal, oral, or inhalational), duration of exposure, and the species tested. The effects, which are also called endpoints, could range from outright signs of toxicity, e.g., vomiting, to subtle signs, e.g., weight loss. Effects may not be observable unless tissues are dissected or functional enzymes are measured. For example, the endpoint considered most predictive of organophosphate (OP) insecticide toxicity is inhibition of a group of enzymes called cholinesterases that are present in the brain, nerves, muscles, and blood. All signs and symptoms of OP insecticide poisoning are preceded by inhibition of these enzymes. Because inhibition of cholinesterases is the most sensitive endpoint caused by the lowest OP doses, it is used to establish the NOEL. (See related article in this issue, p. .) Two basic categories of studies are conducted: acute and chronic. Acute exposure studies administer single doses of a pesticide in patches attached to the skin, in the food or water, or in the air. The studies are short-term and the doses are usually high enough to cause serious adverse effects. Acute toxicity testing generates the LD50, the dose lethal to 50% of the test organisms, usually rats or mice. The chronic exposure studies are designed to determine the risk over a lifetime of exposures. Rats and/or dogs are fed different pesticide doses daily for 90 days, one year, and two years. Overt signs of toxicity are recorded during the study, and at the end the animals are sacrificed to measure enzyme activities and tissue pathologies. The FQPA requires special attention be paid to the possibility that infants and children may have enhanced susceptibility to a pesticide compared to adults. This requirement is met by studying neurotoxicological, developmental, and reproductive effects. The neurotoxicological studies examine everything from effects on posture and gait to alterations in normal behavior. In the developmental studies, pregnant rats and newborns are fed different doses to determine potential abnormal growth and defects in organs and bones. The reproductive toxicology studies involve feeding adult rats different doses of pesticide, allowing them to mate, and then examining the viability of offspring and their potential for successful mating. Environmental Chemistry Determines the Potential for Exposure Monitoring the amounts of chemical residues in the environment is a fundamental activity of environmental chemistry and is essential for exposure assessment. Residues in food, water, air, and soil will be highly variable depending on environmental conditions during and after the application of a pesticide. EPA is currently using mathematical simulation models to predict pesticide residues in water and air, but reliable models are not available to predict residues in food. Therefore, residues in food, especially after preparation by the consumer, would need to be measured for an accurate exposure assessment. Instead, EPA typically assumes that all residues are equal to the tolerance, which is always going to be much higher than actual residues. EPA will also assume 100% treatment of all acreage of the crop for which a registration is requested, unless actual number of acres treated are known. The companion element to monitoring is determining quantities of specific foods eaten. The EPA obtains this information from the USDA National Food Consumption Surveys (NFCS). These surveys record the amounts of different foods eaten for up to three days by individuals of different ages. For exposures related to residential use of pesticides (e.g., termite and cockroach treatments, lawn and garden use), human behavior in and around the house help determine contact time with residues and the potential for the residues to be transferred to the skin or respired. EPA is especially interested in studies that simulate the play behavior of infants as they crawl around the house and touch various surfaces. Combining the NOEL and the Exposure to Estimate Acute Exposure Risk Actual exposure, which is expressed in the same units as the NOELmicrograms of pesticide (g) per kilogram of body weight (kg) per day (d)is determined by multiplying the residues in food and water by the amounts consumed in a day. The result, micrograms of pesticide, is then divided by the body weight of different age classes. For example, a two-year-old child is assumed to weigh 10 kg and a male adult is assumed to weigh 70 kg. EPA separately estimates the risk of harm from acute (single high-end) and chronic (average daily) exposure. For each type of exposure, the specific residue and food consumption inputs differ greatly and thus influence the risk assessment outcome. For the acute exposure risk, EPA first assumes that residues in food are at the level of the tolerance and all acres of crops are treated. This type of assessment is called the Theoretical Maximum Residue Contribution (TMRC). Alternatively, EPA can adjust the theoretical residue levels downward for already registered pesticides by factoring in the actual percentage of acres treated. The agency could also substitute the theoretical levels with the highest levels found in field trials. In a number of recently released OP risk assessments, EPA seems to rely solely on the TMRC method to generate food residue numbers. Potential exposure to the high-end residues is estimated using the distribution of food intake available from the USDA NFCS. The NFCS represents over 90,000 individual dietary habits per day. The highest residue in each food item is multiplied by each of the 90,000 potential daily diets to yield a distribution of exposures for each classified age group. Statistical analysis of this distribution yields for the US population a high-end exposure that comprises 99.9% of all exposures. To estimate the acute dietary and drinking water risk, EPA compares the highest theoretical level of exposure generated in the TMRC to the NOEL, usually measured in an acute exposure study. The NOEL is divided by the theoretical exposure to calculate a Margin of Exposure (MOE). If this MOE is greater than 100, then EPA will conclude that the theoretical acute exposure is of no concern. EPA will also factor in potential exposure in drinking water based on child (one liter per day) and adult (two liters per day) consumption patterns to determine if it significantly changes the MOE. Any residential exposure could also be incorporated into the MOE, but standard methods for obtaining these data are less developed than for food exposures. Estimating Chronic Exposure Risk Chronic exposure risks use average food consumption data and realistic food residue values, known as the anticipated residue concentrations (ARC). The average exposure is calculated and then compared to the reference dose (RfD). The RfD is actually the NOEL from chronic feeding studies divided by an uncertainty factor of 100, sometimes called a safety factor. The safety factor accounts for uncertainties in extrapolating the rat or dog NOEL to humans and in extrapolating effects from adults to children. If children are deemed to be more susceptible than adults, then up to an additional tenfold factor might be incorporated into the RfD calculation. EPA feels that any exposure that does not exceed the RfD has a reasonable certainty of causing no harm over an individuals 70-year lifespan. If the MOE and RfD are exceeded for aggregate exposures, then EPA may require a registrant to mitigate the exposure. Mitigation could come in the form of lowering tolerances, changing maximum application rates, changing use practices, or in the case of occupational exposures, requiring certain protective garments. The Azinphosmethyl (Guthion) Risk AssessmentConsumer Exposures EPA has been focusing its post-FQPA risk assessments on already registered OP insecticides; it recently released preliminary re-registration eligibility decision documents (REDs) for sixteen compounds. The REDs represent the results of the risk assessment process employing the principles previously presented. In addition to answering the questions posed by the mandates of the FQPA, the REDs also include a risk assessment for workers. A preview of what might be expected for widely used OP insecticides is contained in the azinphosmethyl RED. Azinphosmethyl, heavily used on apples and pears, represents a simple case for aggregate exposure assessment because the compound has no registered residential uses. Thus only exposures for food and water needed aggregation. Water exposures, however, were a tiny fraction of dietary exposure; aggregating them to calculate acute and chronic risk did not change EPAs conclusions. In the RED, EPA first defined the NOELs used for acute and chronic dietary risk. The NOELs were based on the lowest dose causing statistically significant inhibition of blood cholinesterase. The acute NOEL could not be determined from the appropriate acute single dose study, but the lowest observed effect level (LOEL) was 1000 g/kg/d. For calculation of the acute MOE risk, EPA applied a benchmark of 300 (instead of 100) to make up for the lack of a NOEL. The NOEL for chronic risk was 150 g/kg/d based on a one-year feeding study using dogs. The EPA concluded that children were not likely to be more susceptible to azinphosmethyl than were adults; thus, no extra safety factor was needed to calculate the RfD. Also, azinphosmethyl was negative in carcinogenicity tests. The RfD was calculated to be 1.5 g/kg/d. To estimate acute dietary risk, the EPA used the TMRC approach. As a result, the calculated MOEs, ranging from 3 for children to 17 for males older than 13 years, failed the test for safety. EPA concluded azinphosmethyl in the diet represents a serious risk concern for acute exposure both for existing and proposed uses. Azinphosmethyl passed the tests for chronic exposure risk with flying colors. Infant exposure was estimated to be 54% of the RfD, while exposure to the general population was only 13% of the RfD. EPA concluded there was no risk concern with average daily consumption of azinphosmethyl residues. Azinphosmethyl and Worker Exposure Risk to workers was projected for fourteen different applicator exposure scenarios (including mixing and handling) and for post-application activities (propping, thinning, harvesting). The NOELs from dermal and inhalation exposure studies were used to predict occupational risk. The resulting MOEs, aggregated for dermal and inhalation exposures, failed to meet the EPA safety benchmark, even when personnel protective equipment was used. Protective equipment was considered to be gloves and double layered clothing. Post-harvest activities, even with consideration of the current reentry intervals, all failed to meet the MOEs. EPAs detailed analysis of worker exposure will be discussed in a future issue of AENews Reality CheckWhat Does It All Mean? While consumers and worker exposures to azinphosmethyl are estimated to be below the NOEL for all scenarios, EPA becomes very concerned if MOE is not greater than 100. An MOE of 100 is equivalent to the RfD, and only chronic exposure meets this safety benchmark. One could argue that because occupational exposures are voluntary, an MOE greater than the NOEL but less than 100 is acceptable. Exposures to consumers are involuntary, so the risk managers at EPA seem most comfortable with a very large MOE. It is clear from EPAs analysis, however, that unacceptable acute exposure resulted solely from use of unrealistic residue inputs. Granted, it seems logical to want to know how many consumers might be exposed to the highest possible level of pesticide residues on any one day. But the reality of potential exposure, as determined from USDA pesticide use surveys and food residue monitoring studies, definitively prove that 100% of all crop acres are not treated and nearly 95% of crop samples are less than 10% of the tolerance levels. Thus, failure to meet the 100-fold safety benchmark using unrealistic input data is overcome by the reality of the daily exposure, even considering high-end exposures. The bottom line on resolving this issue is determining a realistic and appropriate high-end exposure. Industry has within the power to affect a solution. In two wordsMORE DATA. OFmsI(J(,,L6o6F9k9>H*6>*65-OP]yz & ' stghFG$-OP]yz & ' stghFG()M#N#7%8%'(((I(J(**,,¾} |  J  K         d ./    s t  gh    0()M#N#7%8%'(((I(J(**,,,,//00i2j2,,,//00i2j2335 5K6L6o6p6E9F9k9l9::0>1>H>g>>>>>>>>>¼򧧧򥥥            S  T            ;  { "j2335 5K6L6o6p6E9F9k9l9::0>1>>/ =!"#$%* N,*?'c @(76c{f뚡j F^Q(% D:Z5]t0,sr[gW]׍Rl`h}Q[ѱv3}醙ޝȆ baiquWGyPq/ ^"xY !XYTĀQ D /^wwN]jwPs9UְUB#OaW?JT_B'-9;\R~.-7wNe`>L^z 0W:ҭ0_@)TgaOYDax%~_k T=(B\ GG]0[XA| [(@(NormalCJmH 0`0 Heading 1$@&5<A@<Default Paragraph Font8C`8Body Text Indent:P!     9 #j.9::l>"j2>#%',>$&1?AH 1.1:::"-0KNY    003&333e5i5::: Allan FelsotPHard Disk:Word:Manuscripts:Agrichem Environ News:A&EN 11/98 Anatomy Risk Guthion Allan FelsotPHard Disk:Word:Manuscripts:Agrichem Environ News:A&EN 11/98 Anatomy Risk Guthion Allan Felsot/Hard Disk:Temporary Items:Word Work File A 1270 Allan FelsotPHard Disk:Word:Manuscripts:Agrichem Environ News:A&EN 11/98 Anatomy Risk Guthion Eric BechtelKMacintosh HD:AE Newsletters:November98:Articles:EDITED Anatomy Risk Guthion Eric Bechtel<Macintosh HD:Temporary Items:AutoRecovery save of EDITED Ana Eric Bechtel<Macintosh HD:Temporary Items:AutoRecovery save of EDITED Ana Eric Bechtel1Macintosh HD:Temporary Items:Word Work File A 454 Eric Bechtel1Macintosh HD:Temporary Items:Word Work File A 454 Eric Bechtel2Macintosh HD:Temporary Items:Word Work File A 1774@::::v:P@GTimes New Roman5Symbol3 Arial3Times"1h]j*F2{*i1 1%1 1%$0d);); >OAnatomy of a Risk Assessment Under the FQPA: The Azinphosmethyl (Guthion) Case Allan Felsot Eric Bechtel텐&&UxvzQ#y =*nDWV\+MiE,]3LH'[o0u+k@RѾ z<5zmI_daI(6F`.v1)"%ѦVXZ罤UZS '2JݜmM]i {Wði?-T*tZ)@p*L(t=jJhD*i`V V&&{00020941-0000-0000-C000-000000000046}Endnotes\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0V V&&{00020940-0000-0000-C000-000000000046}Comments\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0V V&&{0002093F-0000-0000-C000-000000000046}Footnote\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0V V&&{0002093E-0000-0000-C000-000000000046}Endnote\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0V V&&{0002093D-0000-0000-C000-000000000046}Comment\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0V V&&{0002093C-0000-0000-C000-000000000046}Borders\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0T T&&{0002093B-0000-0000-C000-000000000046}Border\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0V V&&{0002093A-0000-0000-C000-000000000046}Shading\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0` `&&{00020939-0000-0000-C000-000000000046}TextRetrievalMode\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0^ ^&&{00020937-0000-0000-C000-000000000046}AutoTextEntries\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0\ \&&{00020936-0000-0000-C000-000000000046} AutoTextEntry\ \ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0T !T&&{00020935-0000-0000-C000-000000000046}System\ "\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r #rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0X $X&&{000 ՜.+,D՜.+,P hp  0'Washington State University%);: PAnatomy of a Risk Assessment Under the FQPA: The Azinphosmethyl (Guthion) Case Title 6> _PID_GUID'AN{21817104-6143-11D2-8767-A7B9EAA462F6}8.0Z *Z&&{000209A4-0000-0000-C000-000000000046} _OLEControl\ +\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r ,rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0T -T&&{00020930-0000-0000-C000-000000000046}Fields\ .\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r /rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0T 0T&&{0002092F-0000-0000-C000-000000000046}Field\ 1\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r 2rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0V 3V&&{0002092E-0000-0000-C000-000000000046}Browser\ 4\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r 5rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0T 6T&&{0002092D-0000-0000-C000-000000000046}Styles\ 7\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r 8rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0T 9T&&{0002092C-0000-0000-C000-000000000046}Style\ :\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r ;rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0T <T&&{0002092B-0000-0000-C000-000000000046}Frames\ =\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r >rTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0T ?T&&{0002092A-0000-0000-C000-000000000046}Frame\ @\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r ArTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0X BX&&{00020929-0000-0000-C000-000000000046} FormFields\ C\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r DrTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0X EX&&{00020928-0000-0000-C000-000000000046} FormField\ F\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r GrTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0X HX&&{00020927-0000-0000-C000-000000000046} TextInput\ I\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r JrTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0V KV&&{00020926-0000-0000-C000-000000000046}CheckBox\ L\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r MrTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0V NV&&{00020925-  !"#$%&'(*+,-./02345678:;<=>?@CRoot Entrymmmm۶۶mmmm۶۶mmmm۶۶mmm F۶m۶m۶Kq:Em۶1Tablemmmm۶۶mmmm۶۶mmmm۶۶mmmm۶۶m۶m۶mmmm۶m۶m۶m۶m۶m۶m۶m)mmWordDocument۶۶mmmm۶۶mmmm۶۶mmmm۶m۶mm۶mmm۶m۶m۶m۶m۶m۶m۶P۶mSummaryInformationm۶۶mmmm۶۶mmm(m۶mmm۶mm۶m۶m۶m۶m۶m۶m1m۶DocumentSummaryInformationm۶۶m8۶m۶mmmm۶m۶m۶m۶m۶m۶m۶m9mmCompObjmmmm۶۶mmmm۶۶mmmm۶۶mmmm۶m۶mm۶mmm۶mX۶mmmm۶۶mmmm۶۶mmmm۶۶mmmm۶۶mmmm۶۶mmmm۶mmm۶mm۶m۶m۶m۶m۶m۶m۶m۶m۶mm۶۶mmmm۶۶mmmm۶۶mmmm۶۶mmmm۶۶mmmm۶۶m۶m۶mmmm۶m۶m۶m۶m۶m۶m۶m۶m۶m۶mm FMicrosoft Word DocumentNB6WWord.Document.8ld\ d\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r erTypeLib&&{00020905-0000-0000-C000-000000000046}Version8.0b fb&&{0002091D-0000-0000-C000-000000000046}MailMergeDataSource\ g\ProxyStubClsid&&{00020424-0000-0000-C000-000000000046}r hrTy