1. International Conference on Wildlife Fertility Control
Fertility Control for Wildlife Management: Development of new tools and regulatory issues
Doug Eckery, Darcy Mora, Rick Mauldin, Emily Ruell, Jeanette O’Hare, John Eisemann
International Conference on Wildlife Fertility Control
Washington, D.C., July 2017

2. If the only tool you have is a hammer, you tend to see every problem as a nail
--- Abraham Maslow
NWRC Mission
Apply scientific expertise to resolve human-wildlife conflicts while maintaining the quality of the environment shared with wildlife

3. Fertility Control for Wildlife Management
Davis 1961
Principles of population control by gametocides
26th North American Wildlife Conference
Warren 1995
Should wildlife biologists be involved in wildlife contraception research and management?
Wildlife Society Bulletin
Fagerstone et al. 2002
Wildlife fertility control
Wildlife Society Technical Review

4. Fertility Control – the promise
Reduced frequency and costs of control
Reduced amount of poisons
(environmental contamination, regulatory constraints)
Reduced risk to non-target species
Increased scale of management
More humane to target species
Number of Animals

5. Fertility Control … it’s complicated
New Management Tools

6. NWRC Fertility Control Project
Three main areas of research
Vaccine development
- GonaCon use as a management tool
- improved formulations, e.g. dogs
Chemosterilants (direct acting reproductive inhibitors)
- primordial follicles
Delivery
- mucosal vaccines

7. Best
One Hit, Permanent Sterility

8. Permanent sterility How can we cause oocyte depletion?
Oocyte (egg) depletion
GnRH and ZP vaccines
Ovulation
primordial
follicles
mature follicle
cell death > 99%
How can we cause oocyte depletion?
Through mass activation of all primordial follicles
Directly kill the primordial oocyte and/or supporting cells

9. New molecular targets +/- 2-3 +/+ 1-2 -/- Genotype Ovulation rate
Growth and differentiation factor 9 (GDF9)
Bone morphogenetic protein 15 (BMP15)
Oocyte-derived growth factors
+/-
2-3
+/+
1-2
-/-
Genotype
Ovulation rate

10. Vaccination against GDF9 and BMP15
Deer
Ovulation Rate*
Treatment
Year 1
Year 2
Year 3
BMP15 ↑
GDF9
infertile
* fawns/doe

11. Vaccination against GDF9 and BMP15
Deer
Ovulation Rate*
Treatment
Year 1
Year 2
Year 3
BMP15 ↑
GDF9
infertile
* fawns/doe
Horses
Ovulation Rate**
Treatment
Year 1
Year 2
BMP15 ↓ ?
GDF9 -
Smaller follicle diameter at ovulation, compared to controls
High incidence of abnormal follicles
Decreased number of days in estrus
** ultrasound

12. Functional characterization of primordial follicles
Expression of components involved in internalization of compounds into oocytes
Methods for isolation and culture of follicles and oocytes from ovaries
Key molecules for oocyte function and survival
Chemosterilants
Isolated primordial canine follicles

13. Delivery - mucosal vaccines
Injectable vaccines have limited usefulness for landscape-level wildlife management
Vaccine adjuvants often contain Mycobacterium sp.
- highly immunogenic
- M. avium is ubiquitous and most animals have been exposed
component in GonaCon
Can M. avium be used in a mucosal vaccine?

14. Fragmented M.avium (MAF)-GnRH conjugate
All rats responded to MAF-GnRHconjugate

15. MAF-IMX294 conjugate Treatment n % with GnRH titer
Median titer (x1000)
% Bred
low dose, low freq (3x , biweekly) 10 70
high dose, low freq (3x, biweekly) 60 96 90
high dose, high freq (6x, weekly)
160 40
low dose, high freq (6x, weekly) 50 16
Injected (IM)
100
2048
Negative Control 9 78

16. Fertility Control Product Regulators
Wildlife and Feral Animals
Companion Animals, Livestock
and Zoos
Products for use in wildlife
EPA
FDA

17. Legal Methods of Pesticide Use
Full or Conditional Registration
FIFRA* Section 3
Experimental Use Permits
FIFRA Section 5
Special Local Needs
FIFRA Section 24
Emergency Use Permit
FIFRA Section 18
* Federal Insecticide, Fungicide, and Rodenticide Act

18. National Pesticide Registration
FIFRA Section 3
- Based on both active ingredient and end-use formulation
- Data intensive
- PRIA Fees
- Cost/Benefit evaluation
Does not guarantee use in a state
Widest latitude product classification
EPA has reviewed the data conducted the risk assessment, and looked at the cost benefits of the product
These registrations can be for TGAI, Concentrates or End-Use formulations
Data intensive
Guaranteed review time for a fee
Does not guarantee use in a state
Does make it easier to get a state approval

19. Registered fertility control products for wildlife management
Vaccines
- ZonaStat-H & D (pZP) – horses, burros, deer
- GonaCon (GnRH) – deer, horses, burros
Chemosterilant
- ContraPest® (VCD and triplotide) - rats
Reproductive Inhibitor
- OvoControl® P (nicarbazin) - pigeons

21. Experimental Use Permit
FIFRA Section 5
- Data requirements variable, label, study protocol
- EPA Review
6 months for registered active ingredient
16 months for unregistered active ingredient
- Duration: 1-2 years (sometimes longer)
< 10 acres exempt
State requirements vary
Contraceptive products can also be used under FIFRA Section 5 to conduct experiments
Can be relatively easy to obtain if it the product currently has a registration,
New A.I.s will essentially require a complete registration dataset so they can be data intensive to obtain
Need data, protocol, and a label under which the product can be used.
EPA reviews the package and determine permitting for the study.
Uncommon that EPA issues for extended periods, normally 1-2 years, but contraceptives can be longer
10 acre exemption
States vary as to their acceptance of the 10 acre exemption

22. Regulatory Path - Wildlife Fertility Control Tools
Environmental Protection Agency
FIFRA
State Department of Agriculture
Various state laws and codes
Federal & Tribal Management
Authority
Commonly Accepted Pests or Species not Regulated by States
So where are we at
The mechanisms I outlined provide the framework for managing a pesticide product use below the level of the US EPA
This system seems to function for commonly accepted pest species or Species not regulated by states
By that I mean by state Game and Fish agencies
Hunted species
Furbearers

23. Regulatory Path - Wildlife Fertility Control Tools
Environmental Protection Agency
FIFRA
State Department of Agriculture
Various state laws and codes
State Wildlife Management Authorities
State Regulated
Species
Federally Regulated
Federal & Tribal Management
Authority
Commonly Accepted Pests or Species not Regulated by States
When you are talking about a species that state game and fish authorities have interest in, a whole additional level of complexity enters into the picture
This became very apparent to use with the registration of GonaCon
Opposition from state fish and game from the moment we told them at an AFWA meeting in Snowmass Colorado
Lots of reasons given
Biological implications
Main one Hits them in the pocket book License sales

24. Country – often no EPA equivalent for registration Species
International requests for pesticide product or active ingredient
Detailed description of the project, including the following information:
Country – often no EPA equivalent for registration
Species
Wild/feral or owned/captive?
Number animals to be treated
Dosage
For wild/feral individuals - size of geographic area
Will the application of this otherwise product follow the EPA- approved pesticide label “Directions for Use” exactly?

25. A “Standard” for fertility control
At least 90% effective
Remote delivery
Reversibility (more important for some species than others)
Safe for use in pregnant animals.
No significant health side effects
Agent does not enter food chain
Minimal effects upon individual and social behaviors
Low cost
Species specificity
From “Wildlife Fertility Control: Fact and Fancy” a publication of the Science and Conservation Center at Zoo Montana

26. The ideal fertility control
Technically feasible, cost effective
Acceptable: end-users, public
Gene Drive
Ideal fertility control = proposed fertility control justified differences
‘SAFE’

27. Provides important non-lethal tools for wildlife management
Fertility Control … it’s complicated
Is it a silver bullet?
Will it replace conventional controls?
Provides important non-lethal tools for wildlife management
New Management Tools

28. Acknowledgements Fertility Control Project Collaborators Doug Eckery
Rick Mauldin
Darcy Mora
Kathleen Eddy
Meg Bacon
Lauren Jaebker
Ellen Payton
SpayFIRST! – Ruth Steinberger, Bill Clay, Chuck Helwig
APHA (UK) - Giovanna Massei, Dave Cowan
CSIRO (Australia) – Lyn Hinds
Imaxio (France) – Fergal Hill
Colorado State Univ – Jason Breummer, Jim Graham
Texas Tech Univ – Harvinder Gill
Assiniboine & Sioux Tribes (MT)
Navajo Nation (AZ) – Scott Bender
Wildlife Services (AZ) – Dave Bergman
Victoria Univ of Wellington (NZ) – Wayne Linklater
Hebrew Univ (Israel) – Tal Raz
Funding:
APHIS, SpayFIRST!, BLM, APHA

29. Thanks

30. Special Local Needs Registration
FIFRA Section 24(c)
- State issued
- Use within a single state
- Can be data intensive
- EPA Review: 50 days
- Duration: Indefinite
FIFRA gives states authority to register their own registrations
To meet a Special Local Need
FIFRA Section 24c
Can be a data and review intensive, but generally easier to obtain than a Section 3
It still has to go though EPA approval process – 50 days
Normally time limited, but not always
This is a good option for very local situations
Quick and relatively easy

31. Emergency Use Permit FIFRA Section 18 Economic losses Quarantine
Natural Resource Protection
Public Safety
Crisis
- EPA Review: 50 days
- Duration: 1 year
States also have the authority under FIFRA Section 18 to declare emergencies
Products can be used for unregistered uses to meet economic, quarantine, natural resource protection , or public safety emergencies.
Since these are emergencies a State authority – Dept of Ag.

32. ‘Tools’ for Fertility Control
Surgical
Ovariectomy/castration
Tubal ligation
IUD
Vasectomy
Pharmaceuticals
Progestins, estrogens
Hormone agonists
Prostaglandins
Intra-testicular agents
Chemosterilants
Vaccines
Gonadotropin releasing hormone (GnRH)
Porcine zona pellucida (pZP)