|
     
Cox Companies:
|
HOW
DOES CLEANER AIR AFFECT HUMAN HEALTH AND LONGEVITY?
Many expensive regulatory proposals are based on the belief that
continuing to reduce levels of fine particulate matter in urban air and
mineral dusts in occupational environments will further reduce the burden of
lung diseases and promote longer and healthier lives. But is this
true? In 2011, Cox Associates found that there is likely to be an
exposure concentration threshold for exposure to crystalline silica duet
below which further reductions in exposure have no effects on human health;
conversely, exposures above this threshold can stimulate unresolved chronic
inflammation of the lung, leading to increased risk of lung cancer and
other diseases (www.ncbi.nlm.nih.gov/pubmed/21477084).
Cox Associates also found that current regulatory proposals and benefits
assessments for further reducing fine particulate matter (PM2.5) in urban air
rest on questionable assumptions about causal impacts of exposures on
human mortality rates, and on incomplete uncertainty analysis (www.ncbi.nlm.nih.gov/pubmed/22050234)
WHAT
IS THE ECONOMIC VALUE OF INFORMATION FROM TRACKING CANADIAN CATTLE IMPORTED
TO THE US?
Amid
growing concern about the potential emergence of BSE in North America since
the discovery of a BSE-positive cow of Canadian origin in Seattle
in 2003, there has been debate and litigation over whether, when and how
fully the US
should re-open its borders to the import of Canadian cattle and beef
products. In 2004, Cox Associates led a study for R-CALF (Ranchers-Cattlemen
Action Legal Fund) to identify and apply decision and risk analysis
frameworks to help inform the debate. One of the results is a
Value-of-Information (VoI) framework that suggests
that tracking Canadian-origin cattle in the US may have a high economic value
if additional BSE cases are discovered. This framework and results can be
downloaded here.
WHICH
FOOD-BORNE MICROBIAL HAZARDS MATTER MOST?
In June of 2003, Cox Associates
delivered to the Animal Health Institute (AHI) a new approach to quickly and
accurately rate food-borne microbial hazards and risk management proposals.
The new approach, called the Rapid Risk Rating Technique (RRRT), rates
hazards and risk management interventions based on their probable human
health impacts. These are estimated by multiplying several risk factors,
including relative values for expected contamination exposure frequency,
infectivity, dose-response, and health consequence. Data values are provided
in the methodology.
The new rating methodology is intended
to build upon and refine FDA's proposed Draft Guidance Document #152 while
seeking to overcome some of #152's potential limitations (http://www.fda.gov/ohrms/dockets/ac/03/slides/3919OPH2_01_Cox.ppt
http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3919T2.htm).
Simulation-optimization is used to optimize and validate the performance of
the proposed rating system in identifying the worst problems, taking into
account realistic uncertainties.
The RRRT method can consider human
health benefits as well as risks, account for projected changes in future
antimicrobial resistance rates among multiple bacterial pathogens, and assess
risks for specific human sub-populations. Applications to tetracyclines,
macrolides, ionophores,
and other classes of animal antimicrobials are ongoing.
ARE ANIMAL ANTIBIOTICS TIME BOMBS?
Concern over evolving resistance to
antibiotics among human bacterial pathogens and commensals
due to the use of similar drugs in food animals has been growing in the US, Japan, and the European Union. Biomathematical modeling of the evolution of resistance
has added to this concern by suggesting that continued use even of drugs
(such as virginiamycin) with long histories of safe
use in animals and without apparent significant adverse effects on human
resistance might lead to a sudden increase in human resistance in the future.
An April 2003 draft report by Cox Associates, undertaken with partial support
from Phibro Animal Health to understand and
quantify the potential human health risks, has found that these mathematical
models predict a very low probability of future resistance outbreaks and a
vanishingly small probability of resistance epidemics triggered by continued
use of animal antibiotics and antimicrobials if real, rather than
hypothetical, parameters values are used. Using virginiamycin
as a case study, the report applies techniques of Bayesian uncertainty
analysis to a discrete-event dynamic simulation model with parameters
estimated from data to show that the human health risks are small (much less
than one excess statistical mortality in the whole US population expected
over many years due to emerging resistance caused by animal drug use) with
very high statistical confidence. This analysis based on dynamic simulation
produces quantitative risk estimates similar to those previously obtained by
simpler calculations (www.cox-associates.com/VIRGINIAMYCIN.ppt.)
WHEN ARE LARGER EXPOSURES LESS RISKY?
In May of 2003, as part of a research
initiative supported by the American Chemistry Council, Cox Associates
completed an initial version of an integrated pharmacokinetics-and-pharmacodynamics (PK-PD) simulation model of volatile
organic chemical (VOC) interactions with hematopoietic (blood-forming) stem
cell populations in the bone marrow. Building on an earlier biomathematical model of hematotoxicity
(www.alceon.com/cp99pa2.pdf, http://ehpnet1.niehs.nih.gov/docs/1996/Suppl-6/cox.html),
the new model integrates the homeostatically
regulated responses of normal hematopoietic stem cell populations into a
two-stage stochastic model of carcinogenesis and cytogenetic damage. It is
able to quantitatively simulate, for the first time, the theoretical
cancer-causing potential of different exposure patterns. Initial results show
that cumulative exposures (ppm-years), the most
widely used exposure metric in most epidemiological analyses and statistical
risk models of VOC cancer risks, do not yield accurate risk predictions if
exposure patterns are highly variable. Instead, in addition to the cumulative
exposure, the average concentration within a day, hours-per-day of exposure,
days between consecutive exposures, and length of post-exposure follow-up can
all strongly affect predicted hematotoxic and leukemogenic risks. These factors combine non-linearly,
and their interactions are so strong that they can easily lead to larger
cumulative exposures posing smaller risks (essentially by allowing more time
for the hematopoietic system to adapt to the stress of sustained exposure,
reducing the extent of compensating proliferation and the number of initiated
stem cells formed.) These initial results were presented at the 2003 BELLE
conference on Non-Linear Dose-Response Relationships in Biology, Toxicology,
and Medicine: An International Conference. (University
of Massachusetts, Amherst, MA,
May 28-30th, 2003 www.belleonline.com/abstracts/session6.html).
They appear to be robust to many scientific and modeling and uncertainties.
They suggest a new class of multivariate exposure metrics that can better
explain past animal and human data and better describe the aspects of
exposures that are most useful for predicting occupational and public health
risks from exposures to hematotoxic VOCs. Slides describing these preliminary results can be
downloaded here.
ANIMAL ANTIMICROBIAL RISK ASSESSMENT DO'S AND DONT'S
In February of 2003, Cox Associates in
partnership with the Animal Health Institute prepared a report offering
suggested technical guidance on how to assess human health risks from
antimicrobial drugs used in animal feed additives. The report, entitled
Animal Antimicrobial Feed Additives and Human Health: A Guide to Risk
Analysis, reviews methods and principles for sound and practical risk
analysis in this area, as well identifying practices that should be avoided.
It can be downloaded here.
WHAT DO VOLATILE ORGANIC CHEMICAL (VOC) CARCINOGENS HAVE
IN COMMON?
In January of 2003, Cox Associates
completed a research report on data sources available to support integrated
pharmacokinetics-and-pharmacodynamics (PK-PD)
simulation modeling of cancer risks from mixtures of volatile organic
chemicals (VOCs). This work suggests a framework
for exploiting the common features of many VOC-induced carcinogenic responses
- including Phase 1 and Phase 2 metabolism leading to reactive products
causing cytotoxicity and regenerative hyperplasia,
or other mechanisms of stem cell proliferation - to create a common template
for streamlining the analysis of cancer risks from exposure to the most
common VOCs and their mixtures. Data sources and
technical modeling literature for PK and PD components available to support
such an ambitious attempt at integrated risk modeling are surveyed and
hyperlinks to relevant documents are provided. The report can be downloaded here.
SOCIETY FOR RISK ANALYSIS BEST PAPER AWARD, 2002
In December of 2002, a paper on
"Quantifying human health impacts of antimicrobial risk management
alternatives for enrofloxacin", by Drs. Tony
Cox and Doug Popken of Cox Associates, received a
Society for Risk Analysis Best Paper Award at the Society for Risk Analysis
Annual Conference, New Orleans,
LA. December 9-11, 2002 (www.sra.org/news0203.pdf, page 5). This
paper presented the results of mathematical model validation and extension
efforts originally recommended by Dr. Cox to the FDA in 1999 (http://www.fda.gov/cvm/antimicrobial/vm120999.htm#Anchor-MATHEMATICA-43816).
It also presents initial results of a new simulation model suggesting how
withdrawing an approved animal drug can increase human health risks by
increasing the prevalence of a condition in chickens called airsacculitis that increases the microbial loads of
campylobacter, salomonella, and other bacteria
reaching humans. Finally, it reviews the evidence for and against the widely
accepted hypothesis that chicken is a primary source of campylobacteriosis
in humans - a piece of common wisdom that may have to be revised in light of
data. The presentation slides can be downloaded here.
VIRGINIAMYCIN USE IN CHICKENS POSES MINIMAL HUMAN HEALTH
RISKS
In May of 2002, Cox Associates completed
a quantitative risk analysis of the human health risks that might plausibly
be attributed to the use of Virginiamycin as a
growth promoter in poultry. The risk analysis makes use of a simulation
model, based on extensive human and animal data, that quantifies the number
of human treatment failures, early mortalities, and excess illness-days that
could result from bacteria (vancomycin-resistant Enterococcus faecium, or VREFs) that also acquire resistance to the human drug quinupristin-dalfopristin due to selection pressures from
use of Virginiamycin in poultry. The model uses
recent genogroup and genotype data from amplified
fragment-length polymorphism (Willems et al., 2000,
2001) to show that an extreme upper bound on the number of human lives saved
by an immediate ban on Virginiamycin use in poultry
is less that 1/3 of a statistical life for the entire US population
over the next 5 years. The true number could be zero, if resistance gene
transfer from poultry to humans does not occur.
NEW BOOK ON RISK ANALYSIS
Many theoretical advances and practical
applications of health risk analysis developed at Cox Associates between 1986
and 2001 have been summarized in a recent book on Risk Analysis: Foundations,
Models and Methods (http://kapis.www.wkap.nl/prod/b/0-7923-7615-3).
This advanced text, published in the prestigious INTERNATIONAL SERIES IN
OPERATIONS RESEARCH AND MANAGEMENT SCIENCE, makes full use of contemporary
operations research methods in tackling some of the most difficult and
rewarding problems of risk model creation, validation, and application needed
in current health risk analysis applications. The attached presentation
illustrates a few of the ideas explained in detail in the monograph.
BALANCING "REAL" VS. "THEORETICAL"
RISKS TO CANADIAN BLOOD SUPPLY
Member of different communities of blood
recipients, such as hemophiliacs and immunocompromised
patients, often place different weights on the relative importance of
availability and extremely high safety of blood supplies. This leads to
potential conflicts over policies for addressing the potential risks from
emerging threats, including prion-borne (vCJD, or mad cow disease related) contamination.
Proposals to defer donations from blood donors who have visited the United
Kingdom or who may otherwise have been exposed to vCJD
may increase the theoretical safety of donated blood, but may do so by
increasing the risks of shortages and/or contamination from new first-time
donors. In March, 2002, Dr. Cox presented a decision-analytic approach to
making risk-risk tradeoffs and optimizing decisions about blood supply in the
face of large uncertainties about the underlying science and the reality and
extent of threats from prion-related contamination.
The approach calls for the use of simulation models that can be fit to
available data to estimate the probable consequences of alternative risk
management decisions. It provides a framework for defining and choosing the
"best" risk management option even when there are realistically
wide uncertainties about the probable consequences of different choices.
IS PERCHLORATE BAD FOR YOU?
Perchlorate, widely used in rocket fuel, is found as a
drinking water contaminant in California, Nevada, and elsewhere.
While high doses of perchlorate can cause thyroid
tumors and other effects in rats by inhibiting iodine uptake into the thyroid
gland, ultimately leading to compensating cell proliferation and increased
cancer risk, there is no evidence of a comparable carcinogenic effect in
humans. In March of 2002, Dr. Cox participated as an invited Expert Peer
Reviewer at a two-day public meeting in Sacramento
to advise the US EPA on how to maximize the usefulness and validity of its
recent Draft Risk Assessment document for human health effects of perchlorate. A key recommendation was that the EPA risk
assessment needs to address pharmacodynamic
differences between human and rat sequelae of
iodine inhibition in order to realistically explain and predict human health
impacts of perchlorate in drinking water.
WHAT REALLY CAUSES CAMPYLOBACTERIOSIS?
Campylobacter jejuni
is the most frequent bacterial cause of gastroenteritis in the United States
and frequently causes traveler's diarrhea in both developed and developing
countries. Recently, the U.S. Food and Drug Administration (FDA) proposed to
ban a therapeutic drug, enrofloxacin, from
veterinary use in chickens in case such use might increase drug-resistant campylobacteriosis in humans. On March 1, 2002, Dr. Cox
presented new data analyses in Boston, Massachusetts, indicating that eating chicken per se is
not a risk factor for campylobacteriosis in the United States,
contrary to widespread assumptions. Instead, it appears that restaurant
dining is a risk factor, whether or not chicken is eaten, while chicken and
other meats consumed at home are protective against campylobacteriosis.
This finding has dramatic implications for how risks of campylobacteriosis
should be managed. It suggests that banning enrofloxacin
will have little or no human health benefit, but that better restaurant
kitchen hygiene could be important.
Drs. Cox and Popken
of Cox Associates are currently modeling the risks, costs, and benefits
associated with different risk management strategies for campylobacter. Initial
simulation results suggest that a ban on enrofloxacin
may inadvertently increase the microbial load reaching consumers by reducing
uniformity of chickens at the processing plant. In March, this and other
insights from "farm-to-fork" simulation modeling of risks
associated with chicken-borne campylobacter were submitted to the World
Health Organization (see attached link).
ARE PLAYGROUNDS POISONING OUR CHILDREN?
In April, 2002, the Detroit News ran a
story in which Dr. Cox helped to debunk claims by the Environmental Working
Group (EWG) that pressure-treated wood is putting children at risk of cancer
due to the preservative chromated copper arsenate
(CCA). The EWG's conclusions were extrapolated from
a statistically non-valid study in which EWG invited environmental activists
to collect samples without using any standard or reliable sampling plan and
then interpreted the results as representing realistic exposures. In Dr.
Cox's opinion, the EWG study did not fulfill the requirements for a
scientifically credible or useful risk assessment. http://www.detnews.com/2002/editorial/0204/09/a11-460152.htm
CAUSAL MODELING FOR WORKSHOP ON ANTIMICROBIAL RESISTANCE
In October, 2001, Cox Associates
presented initial findings at the Second OIE Workshop on Antimicrobial
Resistance (http://www.oie.int/eng/press/a_051001.htm)
from a new causal model and analysis of case-control data from the Centers
for Disease Control (CDC). Causal modeling indicates that improper restaurant
food preparation, rather than microbial load of Campylobacter in chickens per
se, as has previously been supposed, is likely to be the main driver of campylobacteriosis risks in the US. Indeed,
our independent analysis confirmed and extended previous findings suggesting
that chicken prepared and eaten at home protects against campylobacter risk.
RISK ANALYSIS FOR WORLD HEALTH ORGANIZATION
In July, 2001, Dr. Tony Cox participated
as an independent expert in the World Health Organization's Consultation on
human health risks
from campylobacter (http://www.fao.org/es/ESN/pagerisk/reportCV.pdf).
DO
ANIMAL ANTIBIOTICS INCREASE THE RISK OF HUMAN RESISTANCE?
In February 2001, Cox Associates
delivered to the Animal Health Institute a risk
analysis report on the relation between use of fluoroquinolones
(FQ) to treat critically ill chicken flocks and potential excess
illness-days in the US
population due to increased resistance of Campylobacter jejuni
(CP), a chicken-borne pathogen, to FQ treatments. This report
breaks new ground by applying a dynamic discrete-event simulation
model to quantify the probable health impacts of different risk
management interventions. Its main conclusion is that the
potential health benefits from tighter control of FQ use on farms is
less than 1% of the potential health benefits from relatively modest
changes in processing of chickens. In addition, the report finds
little evidence of a causal relation between FQ use on farms and excess
illnesses or illness-days in humans.
MOLECULAR BIOLOGY OF CHEMICAL LEUKEMOGENESIS FOR BENZENE
In February, 1999, Cox Associates
delivered to Exxon Biomedical Sciences, Inc., a review of the detailed
biological mechanisms by which benzene can cause hematotoxic
damage and induce secondary Acute Myeloid Leukemia in humans. A key finding
from this study is that many of the mechanisms of benzene-induced health
effects are sub-linear at low doses, helping to explain why recent
epidemiological studies do not find the excess leukemias
and health damage at low exposure concentrations (e.g., 1 ppm
or less) predicted from older benzene health risk assessment models.
Top
CLINICAL APPLICATIONS OF
CYCLOPHOSPHAMIDE MODEL?
On December 15th, 1998 a Hematoxicity Modeling Workshop was held at the University
of Ottawa Institute of Population Health (Professor Dan Krewski,
host), in conjunction with the Benzene
State of the Science
Workshop, 1998. The topic of the one-day Hematotoxicity
Modeling Workshop was a review of the simulation model of cyclophosphamide hematotoxicity
developed by Cox Associates for the American Petroleum Institute. Reviewers
included government scientists from EPA and NIEHS, biomathematical
modelers from the Fred Hutchison Cancer
Research Center
and the University of Ottawa, and experts in clinical hematology and
research from the University of Ottawa and the University of Colorado.
Workshop papers will be submitted for publication in 1999. The main finding,
reported to the Benzene
State of the Science Workshop,
was that the model appeared to offer useful, apparently realistic
predictions. An unexpected finding was that several of the expert
hematologists felt that the model might be useful in clinical practice, in
refining dose regimens for chemotherapy patients.
Top
Cox Associates' ongoing applied research
in data mining technologies has recently led to a promising new application:
using data mining algorithms to combine predictions from different expert
systems for predicting which chemicals are carcinogenic without undertaking
expensive experiments to find out. We discovered that the new
prediction-combination technique, which is based on classification trees, can
produce "hybrid" predictions than are more accurate than any
individual expert system's prediction and also than the predictions from
previous combination methods. Click here to
download a technical paper describing the new approach and results.
Top
In September of 1998, Cox Associates
completed a new approach to finding the probable locations of greatest soil
concentrations of contaminants based on soil samples. Traditional geostatistical and sampling and estimation methods such
as kriging do not fully address the problem of
efficient search for buried hazards when the spatial distribution of yield is
highly uncertain. Our new approach adaptively optimizes the search process so
as to continually maximize its expected yield. This can dramatically cut the
sampling costs needed to show that spatial hazards have been adequately
reduced by sampling and remediation efforts. Details may be found in the
attached technical paper. Click here to download
the paper.
Top
Since 1986, Cox Associates has developed
biologically-based risk assessment (BBRA) simulation models and methods for
understanding the human health risks from chemical exposures. A program
developed for the American Petroleum Institute (API) to predict the effects
on blood cells of dosing with the immunosuppressive drug cyclophosphamide
is now available to other researchers from our web site. Click here to download the required modeling software and
documentation.
Top
CAUSAL ANALYSIS AND PUBLIC POLICY: THE CASE OF DIESEL
EXHAUST
In early June 1998, Cox Associates
delivered written comments on behalf of the Engine Manufacturer's Association
to the Clean Air Science Advisory Committee (CASAC) on EPA's recent (2-98)
Draft Risk Assessment for diesel exhaust health risks. The comments address
causation (as opposed to statistical associations) in epidemiological
literature on health risks of diesel exhaust. It concludes that no causal
link between diesel exhaust and human lung cancer has been found.
METHODS: The document provides
references and web links to statistical resources that help untangle
causation from statistical association. This is a novel application of
insights and methods from our data mining and causal forecasting practice
areas.
IMPACT: CASAC has directed EPA to rework
its draft risk assessment to address issues identified in public comments by
Cox Associates and others. The comments document identifies current methods
for overcoming modeling challenges in this area.
For information, please see the attached report.
CLIENT CONTACT: Glenn Keller, Engine
Manufacturer's Association, 312-644-6610
Top
|
