EPA High Production Volume Chemical Program
Concern regarding the lack of publicly available toxicological data for many of the most widely used commercial chemicals in the US prompted the launch of the Chemical Right to Know Initiative in 1998 by former Vice President Al Gore. A key element in this initiative has been a program to gather screening-level health and ecological effects data for nearly 2,800 chemicals produced or imported into the US in volumes of 1 million pounds or more per year––known as "high production volume" or "HPV" chemicals.
- HPV Challenge Program: Announced in 1998 by the EPA, the Chemical Manufacturers Association (now American Chemistry Council), the American Petroleum Institute, and Environmental Defense, the HPV Challenge Program invites companies and/or consortia to submit dossiers of health and ecological effects data for the chemicals they manufacture to EPA’s Office of Pollution Prevention and Toxics. The US program is modeled on a similar international initiative coordinated by the Organization for Economic Cooperation and Development (OECD), which aims to gather vertebrate data for the following eco/toxicological endpoints:
- Acute systemic toxicity (mammalian)
- Subacute (28-day) toxicity
- Mutagenicity
- Reproductive toxicity
- Developmental toxicity
- Acute aquatic toxicity (fish)
- Terrestrial toxicity
Unique to the US HPV program is a set of animal welfare principles developed by the EPA in consultation with animal protection stakeholders. In an October 1999 letter, EPA called on all HPV program participants to:
- "maximize the use of existing and scientifically adequate data to minimize further testing"
- "maximize the use of scientifically appropriate categories of related chemicals and structure activity relationships"
- "not conduct any terrestrial toxicity testing," "not develop any new dermal toxicity data," and "not develop sub-chronic or reproductive toxicity data for the HPV chemicals that are solely closed system intermediates"
- "use in vitro genetic toxicity testing to generate any needed genetic toxicity screening data"
- "allow 120 days between the posting of test plans and the implementation of any testing plans"
To date, approximately 2,200 HPV chemicals have been voluntarily sponsored by some 400 individual companies and 100 consortia. Between 2000 and 2005, up to half (Sandusky et al, 2006) of all test plans filed each year called for new animal testing. Many of these have been judged by animal welfare stakeholders as non-compliant with one or more of the principles above.
Data gathered over the course of the Challenge Program are being made publicly available on the website of the EPA’s HPV Information System (HPVIS).
- HPV Test Rule: The 267 chemicals left unsponsored under the voluntary Challenge Program have been termed "orphans," and potentially subject to a mandatory test rule promulgated under the Toxic Substances Control Act (TSCA), 15 U.S.C. § 2601, et seq. In December 2000, EPA published a Proposed Rule and Notice in the Federal Register "to require manufacturers (including importers) and processors of [37 HPV] chemical substances to conduct testing for acute toxicity; repeated dose toxicity; developmental and reproductive toxicity; genetic toxicity (gene mutations and chromosomal aberrations); ecotoxicity (in fish, Daphnia, and algae) and environmental fate." In March 2006, a Final Rule was published, calling for the testing of 16 "orphan" HPV chemicals.
- Extended HPV Program: In addition to the voluntary HPV Challenge and TSCA test rule, an industry-led initiative was announced in 2005 to address approximately 500 chemicals that have only recently achieved HPV status. However, in contrast to the EPA-driven initiatives, which have focused exclusively on gathering toxicological hazard data, the so-called "Extended HPV Program," or "EHPV asks companies also to provide screening level use and exposure information for all HPV chemicals."
Animal welfare guidance issued under EHPV urges participants to "consider the likelihood of potential human and environmental exposures; make maximum use of appropriate chemical categories (including retro-fitting "new" HPV chemicals into existing categories); conduct comprehensive searches for existing data; coordinate closely with producers and programs in other regions; and use validated non-animal methods where accepted and appropriate. Moreover, by incorporating a use and exposure component, the EHPV Program will provide the type of information necessary for sponsors to justify claims for a reduced data set."
The goal of EHPV organizers is for all data to be public by the end of 2010.
EPA Voluntary Children’s Chemical Evaluation Program
Concern that infants and children may be differentially susceptible to adverse chemical effects during critical periods of development has prompted several US legislative and regulatory initiatives. Among these is the Voluntary Children’s Chemical Evaluation Program (VCCEP), a component of the 1998 Chemical Right to Know Initiative.
VCCEP was officially launched in 2000 as a pilot program to evaluate 23 chemicals to which children have a high likelihood of exposure. As a voluntary initiative, EPA asked companies that manufactured or imported one or more of these substances to provide information on health effects, exposure, risk, and data needs. To date, 35 companies and 10 consortia have committed to sponsor 20 chemicals.
Toxicological information being requested under VCCEP is subdivided among three tiers as follows:
Tier 1:
- Acute systemic toxicity
- Repeated dose toxicity with reproductive and developmental toxicity screens
- Bacterial reverse mutation assay
- In vitro or in vivo chromosomal aberrations or in vivo micronucleus test
Tier 2:
- Subchronic toxicity
- Prenatal developmental toxicity
- Reproductive and fertility effects
- Immunotoxicity
- In vivo chromosomal aberrations or in vivo micronucleus test
- Metabolism and pharmacokinetics
Tier 3:
- Neurotoxicity screening battery
- Carcinogenicity
- Developmental neurotoxicity
Once dossiers of existing toxicological and exposure data are assembled, an independent peer consultation is organized to "provide a forum for scientists and relevant experts from various stakeholder groups to exchange views on the sponsors' chemical assessments and in particular on the recommended data needs." The recommendations of each peer consultation, together with any public comments, are then submitted to EPA’s Office of Pollution Prevention and Toxics (OPPT), which makes the ultimate determination as to whether any additional data are needed.
EPA Endocrine Disruptor Screening Program
Public concern in the mid 1990s that synthetic chemicals in the environment may be interfering with the hormone systems in wildlife and causing reproductive and developmental abnormalities, and that similar damage might be happening to humans, prompted the US Congress to pass the Food Quality Protection Act (FQPA), 21 U.S.C. § 346a, et seq. Among the provisions of this law are the following requirements:
DEVELOPMENT- Not later than 2 years after the date of enactment of this section, [EPA] shall … develop a screening program, using appropriate validated test systems and other scientifically relevant information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect as [EPA] may designate.
(2) IMPLEMENTATION- Not later than 3 years after the date of enactment of this section … [EPA] shall implement the program.
(3) SUBSTANCES- In carrying out the screening program described in paragraph (1), [EPA]--
(A) shall provide for the testing of all pesticide chemicals; and
(B) may provide for the testing of any other substance that may have an effect that is cumulative to an effect of a pesticide chemical if the Administrator determines that a substantial population may be exposed to such substance.
(4) EXEMPTION- Notwithstanding paragraph (3), [EPA] may, by order, exempt from the requirements of this section a biologic substance or other substance if [EPA] determines that the substance is anticipated not to produce any effect in humans similar to an effect produced by a naturally occurring estrogen.
Responsibility for developing a "toolbox" of validated screens and tests for this "Endocrine Disruptor Screening Program" (EDSP) has been delegated to the EPA’s Office of Science Coordination and Policy (OSCP). Following enactment of the FQPA in 1996, EPA created a multi-stakeholder Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to provide the Agency with recommendations regarding:
- "Methods for chemical selection and priorities for screening"
- "A set of available, validated screening assays for early application"
- "Ways to identify new and existing screening assays and mechanisms for their validation"
- "Processes and criteria for deciding when additional tests beyond screening would be needed and how to validate such tests"
- "Processes for communicating to the public about EDSTAC's agreements, recommendations, and information developed during priority setting, screening, and testing"
In its final report to EPA in September 1998, EDSTAC called for the congressionally mandated scope of the EDSP to be significantly expanded to encompass chemical interactions with two or more additional endocrine hormones (androgen and thyroid, as well as estrogen) in not only humans, but also four additional taxonomic groups (birds, fish, amphibians and invertebrates). In terms of structure, EDSTAC proposed a tiered framework to accommodate substances with differing amounts of available data:
- Tier 1 would consist of a battery of relatively rapid, inexpensive, and largely mechanistic screening assays, designed to detect chemical interactions with estrogen, androgen and thyroid hormones in mammalian and fish species
- In Tier 2, substances which appear, on weight-of-evidence, to be endocrine-active may then be subject to multigenerational reproductive toxicity studies in up to five different taxonomic groups.
Following a joint review of the EDSTAC report by EPA’s Science Advisory Board and FIFRA Scientific Advisory Panel, which expressed "concern about the large numbers of animals that would be needed by the EDSTAC program," OSCP undertook to develop and validate the following new and revised screens and tests:
Tier 1:
- Amphibian metamorphosis assay in Xenopus frogs
- Androgen receptor-binding in vitro
- Aromatase inhibition in vitro
- Estrogen receptor-binding in vitro
- Fish reproduction screen
- Hershberger assay in rats
- Intact male assay in male rats
- Pubertal assay in female rats
- Pubertal assay in male rats
- Steroidogenesis in vitro
- Uterotrophic assay in rats
Tier 2:
- Amphibian 2-generation reproduction study
- Avian 2-generation reproduction study
- Fish lifecycle study
- Invertebrate lifecycle study
- Mammalian 2-generation reproduction study
To aid in this work, EPA constituted the Standardization and Validation Task Force (1998-1999), which was later succeeded by the Endocrine Disruptor Methods Validation Subcommittee (2001-2004), and more recently by the Endocrine Disruptor Methods Validation Advisory Committee (2004-2006). In 2006, EPA decided against renewing the charter for a stand-alone endocrine disruptor advisory committee, in favor of a bifurcated approach, whereby specific science/policy questions will be referred to the FIFRA Scientific Advisory Panel, while peer reviews of individual test methods will be managed through external contracts. Another avenue for the validation and peer review of endocrine disruptor screens and tests is through the international work program of the Organization for Economic Cooperation and Development (OECD), in which EPA is an active player.
In a June 2007 Federal Register notice, EPA published a draft list of 73 chemicals for initial screening under the EDSP, noting that "[t]he Tier 1 screening battery is expected to complete peer review and be ready for use in early 2008." Program implementation beyond this pilot phase (i.e., "the testing of all pesticide chemicals," per the FQPA) will then become the responsibility of EPA’s Office of Pesticide Programs.
EPA ToxCastTM
ToxCastTM is a five-year program of the EPA Office of Research and Development’s National Center for Computational Toxicology (NCCT) whose purpose is "to develop cost-effective innovative approaches to prioritize a large number of chemicals in a short period of time for toxicological testing." Using data from modern cell and molecular biology techniques such as automated high-throughput in vitro assays and "omic" (e.g, genomis, transcriptomic, proteomic and metabolomic) technologies, ToxCastTM aims to build computational models to support rapid and accurate predictions of potential toxicological hazards of environmental chemicals.
As an initial proof-of-concept, approximately 300 data-rich substances are being tested in vitro using more than 400 high-throughput and other assays to generate "predictive bioactivity signatures" of potential adverse effects. Results of this phase are anticipated by the summer of 2008. The second phase of the program will "focus on the confirmation and expansion of ToxCastTM predictive signatures, generating [high throughput screening] data on over 1,000 additional chemicals." Finally, EPA proposes to expand ToxCastTM to encompass thousands of environmental chemicals.
EPA TSCA Interagency Testing Committee
The Interagency Testing Committee (ITC) was created in 1977 under the authority of the Toxic Substances Control Act (TSCA), 15 U.S.C. § 2601, et seq., to "identify chemicals regulated by TSCA for which there are suspicions of toxicity or exposure and for which there are few, if any, ecological effects, environmental fate or health effects testing data." Comprised of 16 federal agency members, the ITC provides the EPA Administrator with semiannual reports concerning substances that have been added to or removed from its Priority Testing List. Factors that must be considered by the ITC before recommending a chemical for testing include:
- Quantities of chemicals manufactured
- Quantities of chemicals released into the environment
- Numbers of individuals exposed and duration of exposure
- Extent of human exposure
- Structure activity relationships to known toxic substances
- Available toxicity data
- Reliability of test data to predict hazard
- Availability of testing facilities
Listed substances may be subject to reporting rules under Section 8 of TSCA, which allows EPA to require chemical manufacturers to provide the Agency with basic production and exposure information, along with unpublished health and safety studies.
Since its inception, the ITC has reviewed thousands of chemicals.
National Nanotechnology Initiative
The National Nanotechnology Initiative (NNI) is a federal umbrella program established "to coordinate the multiagency efforts in nanoscale science, engineering, and technology." In 2008 alone, the combined nanotechnology research and regulatory budgets of the 26 federal agency partners in the NNI is projected to reach nearly $1.5 billion. Examples of agency regulatory initiatives aimed at evaluating the human health and/or environmental safety of nanoscale materials include the following:
Environmental Protection Agency
Food and Drug Administration
Nanoscale Science, Engineering, and Technology subcommittee of the White House Office of Science and Technology Policy, National Science and Technology Council
NTP Interagency Committee for Chemical Evaluation and Coordination
Since its inception in 1978 as a vehicle to coordinate toxicology testing programs within the federal government, the National Toxicology Program (NTP) has routinely solicited nominations from the public and scientific community of chemicals or mixtures to undergo toxicological evaluation. Nominations are initially reviewed by the NTP Office of Chemical Nomination and Selection, after which substances not eliminated from consideration are forwarded, along with relevant supporting information from the open literature, to the Interagency Committee for Chemical Evaluation and Coordination (ICCEC).
Comprised of 10 federal regulatory and research agencies, the ICCEC meets semiannually "to evaluate groups of new study nominations and to make recommendations with respect to both specific types of studies and testing priorities." Chemical nominations and ICCEC testing recommendations for new toxicology studies are published in the Federal Register for public comment, after which public feedback and any new data received are forwarded to the NTP Board of Scientific Counselors for a round of review and public comment. ICCEC testing recommendations that are deemed appropriate and feasible are implemented by the NTP at its laboratories at the National Institute of Environmental Health Sciences.
NTP Center for the Evaluation of Risks to Human Reproduction
Established in 1998 as a division of the National Toxicology Program (NTP) and based at the National Institute of Environmental Health Sciences, the Center for the Evaluation of Risks to Human Reproduction (CERHR) is mandated to provide "scientifically-based, uniform assessments of the potential for adverse effects on reproduction and development caused by agents to which humans may be exposed." To this end, CERHR routinely solicits nominations from the public and scientific community of chemicals or mixtures for evaluation for reprotoxic effects.
All nominations are reviewed by the multi-agency CERHR Core Committee, which determines initial priorities based on factors such as production volume, human exposure, availability of public literature, public concern, etc. A notice is then published in the Federal Register announcing candidate chemical(s) and soliciting new data, nominations of qualified individuals to serve on an ad hoc Expert Panel, and public comments in general. An Expert Panel is then convened on the advice of the CERHR Core Committee and a draft report is prepared and circulated for further public comment. A public meeting of the Expert Panel is then organized to receive additional public comment and prepare a final report/monograph. Depending upon the findings of the Expert Panel, additional reproductive and/or developmental toxicity testing may be undertaken by the NTP at its laboratories at the National Institute of Environmental Health Sciences.
NTP Rodent Cancer Bioassay Program
Following the Nixon administration’s declaration of a "war on cancer" in 1971, a standardized carcinogenicity bioassay was developed by the National Cancer Institute to test chemicals on rats and mice to determine whether they cause cancer in these species. In 1978, the Public Health Service Act, 42 U.S.C. § 200, et seq., was amended to require the Secretary for Health and Human Services to "publish a report which contains a list of all substances (1) which either are known to be human carcinogens or may reasonably be anticipated to be human carcinogens, and (2) to which a significant number of persons residing in the United States are exposed." Around the same time, federal agencies came together to create the National Toxicology Program (NTP) as a vehicle to coordinate toxicology testing programs within the federal government. Thus, from 1978 onward, the rodent cancer bioassay program and responsibility for compiling the semi-annual Report on Carcinogens were left in the hands of the NTP.
Since the inception of the cancer bioassay program, more than 550 chemicals and mixtures have been tested in two-species bioassays (an average of approximately 12 such studies per year, each costing $2-4 million). More recently, the NTP has also made a substantial research investment in the development, validation and use of genetically engineered (transgenic and knockout) mice as a less costly and time- and animal-consuming approach to carcinogenicity testing.
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