SBIR-STTR Award

Rodent pests have eaten our food and transmitted diseases to us for millennia. There are an estimated 300 million introduced Norway or brown rats in the U.S. that cause $27 billion of economic losses annually. Historically the strategy has been to kill rat pests through a variety of methods but primarily by using poison baits that are anticoagulant rodenticides. In addition to all of the problems associated with using poison bait, e.g. poisoning nontarget animals/pets, children under the age of 6, and contaminating the environment, poison does not address the problem. A non-lethal strategy that has significant potential to manage rodent pest number is fertility control. But thus far effective control of free-ranging wildlife, such as small, nocturnal rodents, has not been achieved because distribution to dose rats must be via an oral route. The industrial chemical 4-vinylcyclohexene diepoxide (VCD) accelerates the natural process of atresia leading to depletion of rat ovarian follicles causing ovarian failure and permanent sterility. Follicle depletion occurs when VCD is given in repeated intraperitoneal daily doses and on average, complete elimination of primordial/primary follicles and premature ovarian failure occur by day 58 following the onset of dosing and in mice causes infertility. To date VCD induced follicle depletion has been achieved by intraperitoneal administration. However to develop and commercialize a product to cause wild rat infertility it must be given orally in a bait. This Phase I application aims to test the following hypothesis in three specific aims. Oral administration of VCD to rats will lead to complete depletion of ovarian follicle populations, resulting in infertility demonstrating feasibility for development of a fertility control bait for rats. Aim 1. Determine the dose needed to deplete primordial ovarian follicles in rats by oral exposures to VCD. Aim 2. Determine the time course over which VCD completely depletes ovarian follicle populations. Aim 3. Determine the pharmacokinetics of VCD excretion. Results from Phase I experiments will define the dose and duration of VCD exposure necessary to cause complete ovarian follicle depletion. These results will enable us to obtain sufficient information to progress to a Phase II application to develop an oral bait and baiting protocol to manage wildlife rodent populations. Rats are being targeted in these studies, with the understanding that rats are more resistant to VCD than mice. Thus, success with rats, can easily be translated to mice. Furthermore, rats are the primary target pest species based on the enormous economic and significant public health risks they pose both by their contamination and destruction of our food supplies and the dangerous rodenticide control approaches currently being used to manage rat populations. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Public Health Relevance:
Management of wild rats is critical to minimize agriculture and property damage and the spread of infectious diseases. Lethal approaches introduce poison into the environment and consequently are being targeted for removal from over the counter availability. The goal of this project is to provide data to support the feasibility of using the industrial chemical 4-vinylcyclohexene diepoxide (VCD) to ultimately develop an environmentally neutral permanent rodent fertility control bait to manage wild rat populations

Thesaurus Terms:
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In this phase II application, we propose to test the efficacy of our platform technology derived product, ContraPest(R), a chemosterilant rat bait containing 4-vinylcyclohexene diepoxide (VCD), in reduction of the brown rat population in a model urban setting, the subway stations of New York City (NYC). Our phase II application is comprised of 3 aims. Aim 1 is focused on establishing the safety parameters of our technology, including exclusion of non-target species and impact on the environment. Aim 2 is focused on establishing the feasibility of performing pilot studies in NYC using wild caught brown rat populations both from Arizona and from NYC. Aim 3 is focused on performing a series of pilot studies in NYC to test the efficacy of ContraPest(R) bait in reducing the brown rat population in defined areas of the subway stations in NYC. In phase I we successfully demonstrated the efficacy of orally administered VCD in reducing primordial follicle number and litter size in R. norvegicus laboratory rats (the same species as the brown rat of NYC). We also determined that our current agricultural bait formulation (a pellet bait) is highly palatable to laboratory ras and consumption of our bait results in reduction in fertility in females. Current rat control practices in NYC are focused on rodenticide use. Poison packs are thrown off the back of subway trains onto the tracks. This is largely ineffective primarily due to the abundance of more palatable food choices (i.e. trash) and because poison application frequently results in population rebound effects. While there is no ""magic bullet"" to reducing rat pest populations, we believe that our technology can be used as an adjunct to current rodent pest management practices to have a sustainable significant impact on the reduction of the urban brown rat population. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

Public Health Relevance:
Management of urban rats is critical to decrease the incidences of human-rat interactions and thus lower the spread of rodent borne infectious diseases and reduce infrastructure damage. Current control methods such as rodenticides introduce poisons into the environment and are largely ineffective. The goal of this project is two-fold: identify safety issues associated with a chemosterilant bait containing the ovotoxicant chemical, 4- vinylcyclohexene diepoxide (VCD), and to establish baiting requirements necessary to induce subterranean urban rat population reduction in a model setting (the NYC subway). PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Thesaurus Terms:
Address;Agriculture;Animals;Anticoagulant Agents;Anticoagulant Drugs;Anticoagulants;Area;Arizona;Back;Camping;Chemicals;Common Rat Strains;Communicable Diseases;Consumption;Cost Of Illness;Data;Development;Disease;Disease Costs;Disease Outbreaks;Disease Vectors;Disorder;Distress;Dorsum;Drug Formulations;Eating;Economics;Environment;Environmental Pollution;Exclusion;Fecundability;Fecundity;Female;Fertility;Food;Food Intake;Formulation;Goals;Human;Incidence;Infectious Disease Pathway;Infectious Diseases;Infectious Diseases And Manifestations;Infectious Disorder;Infrastructure;Loinc Axis 4 System;Laboratories;Laboratory Rat;Litter Size;Magic;Man (Taxonomy);Methods;Modeling;Modern Man;Navaho;Navajo;New York City;Norway;Norway Rats;Oral;Outbreaks;Pain;Painful;Phase;Pilot Projects;Poisoning;Poisons;Population;Practice Management;Premature Ovarian Failure;Primordial Follicle;Principal Investigator;Process;Production;Rat;Rats Mammals;Rattus;Rattus Norvegicus;Reporting;Research Infrastructure;Rodent;Rodentia;Rodenticides;Rodents Mammals;Safety;Series;Sickness Cost;Site;Southeast Asia;Southeastern Asia;Sterility;Subway;System;Technology;Time;Toxic Chemical;Toxic Substance;Training;United States;Vector (Infectious Agent);Agricultural;Blood Thinner;Commercialization;Developmental;Disease/Disorder;Efficacy Testing;Environmental Contaminant;Environmental Contamination;Experience;Experiment;Experimental Research;Experimental Study;Field Study;Improved;New Approaches;Novel Approaches;Novel Strategies;Novel Strategy;Pilot Study;Poison;Poisoned;Programs;Pup;Research Study;Sterile;Suburb;Suburban;Suburbia;Thrombopoiesis Inhibitor;Tool;Toxic Compound