The Toxicologist - Society of Toxicology

1961 TOXIC EQUIVALENCY FACTORS ARE NOT UNIVERSAL
WITHIN VERTEBRATE CLASSES: EVIDENCE,
MECHANISTIC REASONS, AND REGULATORY
IMPLICATIONS.
E. A. Carlson 1 , C. H. Sutter 2 , T. R. Sutter 2 and J. B. Silkworth 1 . 1 General
Electric, Niskayuna, NY and 2 University of Memphis, Memphis, TN.
At least forty years ago, investigators realized that extreme differences in sensitivity
to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related dioxin-like compounds
(DLCs) exist among animal species. It was also recognized that these chemicals
are invariably found in complex mixtures, leading to approaches for summarizing
the toxic equivalency (TEQ) of such mixtures for risk assessment purposes.
The World Health Organization (WHO) toxic equivalency factor (TEF) scheme,
which compares individual DLC toxicity to that of TCDD, is now used for determining
mixture TEQs. Although it was probably thought initially that species differences
in sensitivity to TCDD and DLCs would be effectively normalized for
congener-specific TEFs by generating relative potency (REP) estimates within experiments,
the WHO panel soon realized that different vertebrate classes required
different sets of TEFs. Sufficient evidence now exists that even within a vertebrate
class, REPs are not universal. Species-specific REPs have been identified in experiments
comparing responses of human and rodent cells, among avian species, and
even among rodent strains. For example, our laboratory has demonstrated a human
REP of 0.002 for 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126), as determined by cytochrome
P450 1A1 (CYP1A1) induction in fresh human hepatocytes and normal
human epidermal keratinocytes (NHEKs), significantly lower than its assigned
TEF of 0.1 (derived mainly from rodent studies). For fresh human and rat hepatocytes,
this species difference extends to genes other than just CYP1A1 and is directly
related to species differences in the aryl hydrocarbon receptor pathway.
Furthermore, using NHEKs, we have demonstrated that such species difference extends
to other congeners. Identified species- and congener-specific REPs are robust,
repeatable, and significant. Such differences call into question the indiscriminant
use of TEFs to predict risk in a species from which they were not derived.
1962 LOW DOSE RESPONSE RELATIONSHIPS FOR NON-
CANCER ENDPOINTS: OZONE, MERCURY, AND
XENOESTROGENS.
L. Zeise 2 , G. Ginsberg 1 and M. S. Sandy 2 . 1 Connecticut Department of Public
Health, Hartford, CT and 2 Cal EPA Office of Environmental Health Hazard
Assessment, Oakland, CA.
The 2009 National Academy of Sciences report “Science and Decisions: Advancing
Risk Assessment” describes different approaches to modeling dose response relationships
– that depend on background exposures (endogenous and exogenous) of
chemicals that contribute to the disease process, ongoing disease processes, commonness
of the disease, and sensitive and vulnerable populations. These factors are
explored with three chemical substances: Ozone, mercury and xenoestrogens.
While potential mechanisms of action may suggest low dose non-linearities at the
individual level (due for example to host defense), this cannot be generalized, because
of variability in exposures and ongoing health and disease processes that can
translate to linear dose response at the population level. Acute, clinical ozone exposure
studies in humans provide evidence of a linear dose response in FEV1 at low
doses. These and other studies suggest that commonly experienced concentrations
are still above the threshold for toxicity, at even the individual level for healthy
adults for some endpoints. For methylmercury neurodevelopmental effects, modeling
and data suggest low dose linearity at the population level. We explore the case
of mercury further by considering the limited epidemiology studies for Hg° from
dental amalgams, potential impacts of methylmercury on low dose observations of
Hg° effects, and other factors. Integration of animal data into low dose modeling of
Hg° effects is explored. For xenoestrogens, background exposures and disease
processes suggest low dose linearity for a variety of effects. These case studies suggest
linear dose response at the population level for environmental exposures, similar
to what has been found for particulate matter and lead.
1963 ANALYZING THE SAFETY OF GULF SEAFOOD AFTER
THE OIL SPILL BASED ON POPULATION SPECIFIC
EXPOSURE SCENARIOS AND INCORPORATION OF
DISPERSANT AND HEAVY METAL TOXICITY
PARAMETERS.
J. M. Gohlke. Environmental Health Sciences, University of Alabama at
Birmingham, Birmingham, AL.
Gulf fishermen are facing a number of challenges since the British Petroleum
Deepwater Horizon explosion, oil spill and cleanup. One challenge is re-instating
consumer confidence in their product. Since the re-opening of closed Gulf waters
420 SOT 2011 ANNUAL MEETING
to fisheries, numerous groups, including members of Congress, non-governmental
organizations, scientists, local fisherman, processors, and chefs, have raised concerns
over the adequacy of the National Oceanic and Atmospheric Administration
(NOAA) and Food and Drug Administration (FDA) protocol for ensuring the
safety of seafood caught in the Gulf. Primary concerns raised include reliance on an
initial smell test and chemical testing only for a select number of polycyclic aromatic
hydrocarbon (PAH) components of oil, as well as questions regarding the
sampling scheme and risk assessment methodology employed. There is considerable
uncertainty regarding the potential for toxicity related to the use of Corexit 9500A
and Corexit 9527, the primary dispersants employed to break up the oil in the
Gulf. For example, the potential for bioaccumulation of components of the dispersant
in finfish, particularly those that are long-lived and at the top of the food chain
is uncertain. Large amounts of heavy metals have also been released into the Gulf.
Recent research suggests oil spills alter natural filtration processes of arsenic, raising
the concern that increased levels of arsenic exposure via seafood consumption may
be an issue. This project details assumptions in the NOAA/FDA methodology and
develops region specific exposure assessments reflecting local consumption patterns,
particularly in potentially vulnerable populations of subsistence fisherman,
pregnant women and young children. In addition, the project focuses on risk characterization
methodologies that estimate composite risk of cancer and non-cancer
endpoints based on toxicity of dispersant components, heavy metal exposure, as
well as relevant PAHs, resulting in novel estimates of levels of concern (LOCs).
1964 CORN OIL AS A CAUSATIVE FACTOR FOR
PROLIFERATIVE LESIONS OF THE FORESTOMACH IN
B6C3F1 MICE EXPOSED BY GAVAGE.
L. M. Plunkett 1 , T. Starr 2 , J. A. MacGregor 3 and A. M. Jonyas 4 . 1 Integrative
Biostrategies LLC, Houston, TX, 2 TBS Associates, Raleigh, NC, 3 Toxicology
Consulting Services, Arnold, MD and 4 Amvac Chemical Corporation, Newport
Beach, CA.
A National Toxicology Program (NTP) cancer bioassay has established that the dose
of corn oil that is routinely administered daily in gavage studies (5 ml/kg for F344
rats) is by itself associated with altered tumor incidence rates. Thus, corn oil is a potential
confounding factor in carcinogenicity testing/ data interpretation. While
mice receive twice the rat dose (10 ml/kg) in NTP corn oil gavage studies, a similar
study of corn oil effects in B6C3F1 mice has not been conducted. Our previous
work has implicated daily administration of corn oil by gavage as a causative factor
for proliferative lesions of the forestomach in B6C3F1 mice. In the present analysis,
the role of corn oil was examined by comparing tumor incidence rates in mice exposed
to corn oil or water via gavage. A rigorous statistical assessment of heterogeneity
was conducted using mouse forestomach hyperplasia and tumor incidence
rates as reported for control groups of mice in the NTP bioassay series. Results were
compared with those from our earlier analyses that assessed heterogeneity among
control group incidence rates for studies using dietary and inhalation exposure
routes. The combined analyses reveal significantly lower incidence rates of
forestomach lesions in control groups of mice exposed via water gavage, the diet, or
by inhalation, as compared to the rates of these lesions in corn oil gavage studies.
The combined analyses show that daily gavage with corn oil can be a causative factor
for proliferative forestomach lesions in B6C3F1 mice, and that corn oil by itself
is a significant contributing factor in mouse forestomach lesion development.
1965 ASSESSING RISKS FOR SEC- AND TERT-
BUTYLBENZENE: A SURROGATE METHOD.
N. Y. Wang 1 and C. J. Moudgal 2 . 1 National Center for Environmental Assessment,
U.S. EPA, Cincinnati, OH and 2 Environmental Risk & Toxicology, ICF
International, Dublin, CA.
As part of the U.S. Environmental Protection Agency’s (U.S. EPA) mission to protect
the environment, chemicals-of-concern (CoCs) at Superfund or other hazardous
waste sites are cleaned up based on their potential toxicity to humans and
the surrounding ecosystem. However, often CoCs have limited or no toxicity data
to assess their impacts on human health or the ecosystem. In these instances the application
of alternative approaches, such as Structure-Activity Relationship (SAR)
can be considered in conjunction with supporting data such as toxicokinetic and
chemical class-specific toxicity data to identify suitable surrogates for CoCs. secand
tert-Butylbenzenes are two CoCs from the alkylbenzenes class of chemicals that
have very little relevant toxicity data for risk assessment purposes. We propose a
SAR-based surrogate application for sec- and tert-butylbenzenes by using a combination
of toxicokinetic and class-specific toxicity data. Three potential structural
and metabolic surrogates for sec- and tert-butylbenzene were identified: ethylbenzene,
n-butylbenzene, and isopropylbenzene. While these potential surrogates exhibited
some similarity in toxicokinetic characteristics and toxicity manifestation,
the branched alkylbenzenes, which include isopropylbenzene and sec- and tert-