The Toxicologist - Society of Toxicology

1525 SAFETY ASSESSMENT OF FOOD AND FEED FROM
BIOTECHNOLOGY-DERIVED CROPS WITH
MODIFICATIONS THAT REGULATE ENDOGENOUS
GENE EXPRESSION.
J. S. Petrick 1 , W. Parrott 2 , B. Chassy 3 , J. Ligon 4 , L. Meyer 5 , J. Zhou 6 , R.
Herman 7 , B. Delaney 8 and M. Levine 9 . 1 Product Safety Center, Monsanto
Company, Saint Louis, MO, 2 Crop and Soil Sciences, University of Georgia, Athens,
GA, 3 College of ACES, University of Illinois, Urbana, IL, 4 Bayer CropScience,
Research Triangle Park, NC, 5 Syngenta Biotechnology, Inc., Research Triangle Park,
NC, 6 Johnson & Johnson, Raritan, NJ, 7 Dow AgroSciences, Indianapolis, IN,
8 Pioneer, A DuPont Company, Johnston, IA and 9 International Life Sciences Institute,
Washington, DC.
Agricultural biotechnology traits in development include those using tools such as
transcription factors and RNA interference (RNAi) to modulate endogenous plant
gene expression for the improvement of yields, tolerance to biotic and abiotic
stresses, and nutritional quality. Biotechnology-derived crops are presently evaluated
for food and feed safety relative to a conventional comparator according to an
internationally-accepted safety assessment paradigm. This robust and comprehensive
approach incorporates basic concepts from food safety, toxicology, nutrition,
molecular biology, and plant breeding and has been used effectively by scientists
and regulatory agencies for nearly 15 years. The main aspects of the comparative
safety assessment process are reviewed and recommendations are provided for scientifically
sound principles to evaluate the safety of biotechnology-derived crops
developed using biological approaches that modify endogenous plant gene expression.
Key considerations for applicability of the existing safety assessment process
include: 1) The history of safe consumption of RNAi- mediating small RNAs (e.g.,
miRNAs) and regulatory proteins such as transcription factors; 2) The growing scientific
literature describing the central role that RNAi and transcription factors
have played in plant domestication and conventional breeding; 3) Crops engineered
using RNAi constructs are not expected to produce heterologous proteins;
4) Modulation of plant gene expression may result in quantitative differences in
levels of endogenous plant components (but not de novo components) that can be
assessed through compositional analysis.
1526 USE OF CLUSTER ANALYSIS IN PESTICIDE INERT
INGREDIENT RISK ASSESSMENT.
A. S. Duggan 1 , J. Johnston 2 , J. Messina 2 , K. Akkari 3 , D. Hillebold 4 , G.
Lindner 5 and P. McCain 6 . 1 Health Practice Center for Toxicology and Mechanistic
Biology, Exponent, Inc., Philadelphia, PA, 2 Health Practice Center for Chemical
Regulation and Food Safety, Exponent, Inc., Washington, DC, 3 APD/RD, BASF
Corp., Research Triangle Park, NC, 4 Surface Chemistry, Akzo Nobel, LLC, Chicago,
IL, 5 Crop Care Applications, Croda, Inc., New Castle, DE and 6 Regulatory Affairs,
Syngenta Crop Protection, Inc., Greensboro, NC.
The poster illustrates the use of read-across methodology and dietary risk assessment
for oleochemical surfactants that are used as inert ingredients in pesticide formulations.
The August 9, 2006, revocation of 130 food tolerance exemptions resulted in
unprecedented challenges for EPA and industry (pesticide registrants and surfactant
manufacturers) to evaluate reproductive and developmental toxicity for more than
20 classes of inert ingredients within three years. Structurally similar compounds
have similar physical, metabolic and toxicological properties. It is possible to bridge
(read-across) results from one compound to others within a defined cluster of chemically-related
compounds. EPA and the OECD applied cluster analysis in the High
Production Volume (HPV) Programs to reduce the number of toxicity tests, laboratory
animals and the time required to review the study data. The same methodology
was successfully used to conduct OECD 422 Studies (Combined Repeated Dose
Toxicity Study with the Reproduction/Developmental Toxicity Screening Tests)
data development plans. The OECD 422 test results were used in conjunction with
the EPA screening-level dietary exposure model for inert ingredients (I-DEEM) to
assess dietary exposure and risks for the US population, adults and children. The
methodology was validated and resulted in the successful reassessment and retention
of the food use tolerance exemptions of the inert ingredients.
1527 OPTIONS FOR INCREASED REGULATORY
OVERSIGHT OF COSMETICS IN THE U.S.
N. Beck 1 , K. Sullivan 1 and C. Willet 2 . 1 Physicians Committee for Responsible
Medicine, Washington, DC and 2 People for the Ethical Treatment of Animals,
Norfolk, VA.
Cosmetics have recently become one of the focal points of efforts to strengthen
chemical regulations in the US. Under the current law, cosmetics manufacturers are
responsible for substantiating the safety of their products, but for most ingredients,
328 SOT 2011 ANNUAL MEETING
specific toxicity testing is not required, nor is pre-market approval from the Food
and Drug Administration (FDA). Concern over the long-term safety of cosmetics
has prompted legislative efforts to increase oversight. Emerging regulatory models
in the US were analyzed, namely the “FDA Globalization Act of 2009” and the
“Safe Cosmetics Act of 2010.” Specifically, each bill’s approach to hazard and risk
assessment, was examined, including their flexibility in information requirements
and potential for incorporating evolving science. Then, current US cosmetics regulations
were compared with international approaches, revealing broad agreement
overall. Finally, the proposed US models were addressed in the context of the EU’s
distinctive position on animal testing. EU law gradually phases out the use of animals
for cosmetics testing, with a complete ban on the marketing of animal-tested
products by 2013. The market ban presents significant implications for trade with
the EU, which should be considered when drafting new legislation in the US. The
testing and marketing prohibitions in the EU have also impacted the state of regulatory
toxicology, with the impending ban serving as a tool to drive progress in the
development of in vitro and in silico test methods. In order to efficiently assess cosmetic
ingredients and advance international harmonization, proposals to reform
US cosmetics regulations should seek to facilitate the development of modern, harmonized
approaches to testing and assessment.
1528 THE SHE CELL TRANSFORMATION ASSAY—ITS USE
IN HAZARD AND RISK ASSESSMENT FOR REACH.
A. H. Poth. Genetic and Alternative Toxicology, Harlan Cytotest Cell Research
GmbH, Rossdorf, Germany.
The 2-year bioassay is the standard method for carcinogen detection which is time
and resource intensive. Many short-term test, especially genotoxicity tests have
been developed to aid in identification of potential carcinogens. However, the endpoint
of theses systems is genotoxicity and their concordance between rodent bioassays
is only about 60% and a battery of short-term genotoxicity tests can not improve
the overall concordance. In vitro cell transformation tests using SHE- and
Balb/c3T3-cells simulate the process of animal two-stage carcinogenesis. These tests
are suited for the in vitro detection of a carcinogenic potential of test compounds in
safety and risk assessment. Results from cell transformation assays can provide information,
which in combination with data from other testing methods, are useful
for identifying the carcinogenic potential of chemical compounds. The results of
these assays in combination with other information such as genotoxicity data,
structure activity analysis, in vivo toxicity data and pharmaco-/toxicokinetic information
can facilitate a relatively comprehensive assessment of a carcinogenic potential
of a chemical. For prediction of the carcinogenic potential of compound the
SHE cell transformation assay is included in the endpoint specific guidance document
for REACH. In the first phase of REACH (substances > 1000 tonnage per
year), data of the SHE cell transformation were included in the hazard and risk assessment.
Case studies are provided for heavy metal powders and alloys, where the
SHE cell transformation data were used for mechanistic investigations beside other
in vitro test systems. SHE cell transformation data are also provided of a chemical
class (aromatic amines) where genotoxicity data do have only limited value and for
a compound with an structural alert for carcinogenicity (pararosaniline derivatives),
where SHE cell transformation data were used to demonstrate the similarities
across a chemical category.
1529 DEVELOPMENT OF A HEALTH RISK-BASED SURFACE
CONTAMINATION CLEAN-UP STANDARD FOR
OCCUPATIONAL EXPOSURE TO BERYLLIUM.
P. Damian. SCS Engineers, West Sacramento, CA.
A health risk-based surface contamination cleanup standard (SCS) for beryllium
(BE) was developed to facilitate the safe transfer of property (equipment and buildings)
previously used in BE-related processes. Previous SCSs for BE were primarily
based on Department of Energy (DOE) housekeeping criteria rather than health
risks. Quantitative health risk assessment methods were used to develop an occupational
SCS that explicitly considers the relevant exposure pathways and toxicity
endpoints, including both cancer and non-cancer endpoints. For the cancer endpoint
at the 1E-06 risk level, the analysis resulted in an SCS of 17 μg/100 cm 2
based on resuspension of settled dust and subsequent inhalation exposure only (BE
is regulated as a carcinogen by the inhalation route only). For the non-cancer endpoint,
the analysis resulted in an SCS of 0.07 μg/100 cm 2 based on dermal absorption,
incidental ingestion following dermal contact, and inhalation. The non-cancer
SCS was determined virtually entirely by the dermal absorption exposure
pathway, with negligible contributions from the incidental ingestion and inhalation
pathways. This analysis shows that application of the non-cancer SCS in BE monitoring
and control programs will adequately protect workers from both the cancer
and non-cancer health effects of BE when surface contamination is the primary
source of BE exposure.