2(2-e)-(-3)(e-4)=-3e-4)?

Question

expand by using the distributive property. write all the answers with all positive exponents

Answer 1

Use of
Human Data in
Perchlorate
Risk Assessment
EPA’s conclusions regarding the quality of the human data.
EPA misinterpreted epidemiological and statistical data and included unsupported
speculations regarding sources of potential confounding, leading to minimal use of
important data.
· The perchlorate human database is stronger than many on IRIS, as evidenced by
estimations of overall confidence, size of uncertainty factor, and types of available data.
US EPA’s proposed perchlorate RfD based on animal data suggests that perchlorate is
more toxic than several known human toxicants, including methylmercury. However,
these conclusions are not supported by the human data, which consistently show no effect
associated with perchlorate exposure.
· EPA’s human data policy should not be applied to prevent use of clinical studies in
designating a NOAEL for perchlorate because: the perchlorate assessment is a scientific
assessment rather than a regulatory decision, the Greer study is not a “third-party” study
since EPA was intimately involved with the design of the study, and the EPA used the
Greer study in the PBPK models.
· The Greer study does not raise ethical concerns posed by EPA’s human data policy
because it meets the three major requirements of the Common Rule -- review and
approval by an Institutional Review Board (IRB), informed consent, and written
assurance by government agencies of compliance with Common Rule requirements.
· A thorough QA/QC audit conducted on the Greer study showed no findings that would
prevent the Greer study from being used for risk assessment purposes. The response to
the TRS audit report demonstrates the study investigators intimate familiarity with the
key aspects of this study, suggesting that the study was well- managed overall, even
though a number of errors, omissions, and protocol deviations occurred.
Toxicology Excellence for Risk Assessment 3/1/3 2002
Introduction
A primary point for discussion regarding EPA’s risk assessment for perchlorate is the choice to
base the risk assessment on the animal data. In our opinion, EPA erred in discounting the quality
of the epidemiological, clinical, and occupational studies conducted on perchlorate (Appendix
A). The quality of the body of human data is equal to or better than that used in many other
RfDs based on human data. And for perchlorate, dramatic differences in the response of rats and
humans to inhibition of iodine uptake (TERA, 2002) suggests that using animal data as the basis
of the risk assessment will introduce an unnecessary degree of uncertainty that can be reduced by
relying on the human data.
We understand that the EPA has adopted an interim policy on the use of human data and has
postponed conclusions regarding the use of human data for the perchlorate risk assessment until
the NAS provides a report and recommendation on this issue. We further understand that the
EPA does not intend to use this forum to address this issue. We assert, however, that it is not
possible to adequately address a risk assessment for perchlorate without taking into account the
considerable human clinical data. When the policy is clarified by the NAS or future EPA
decisions, the assessment will have to be re-evaluated in light of all of the data.
Therefore, these comments address the following issues:
· Historical use of human data by EPA and evaluation of the quality of the perchlorate
human data compared to other human-data based RfDs
· Assessment of why the human clinical data does not fit within EPA’s human data policy
· Compliance of the key clinical study with the Common Rule requirements
· QA/QC audit of the key clinical study
Historical Use of Human Data by EPA
EPA’s policy when developing RfDs in many of its program offices, regional offices, and ORD
has been to use human data first and foremost in the determination of critical effect and choice of
uncertainty factors. Because of this policy, EPA risk assessment guidelines and guidance
documents have consistently supported the preferred use of adequate human data over that from
laboratory animal data in the estimation of risk values such as RfDs (EPA 1989, 1991, 1993,
1998, 1999; Barnes and Dourson, 1988; Dourson, 1994) and RfCs (EPA, 1994; Jarabek, 1994,
1995). This preference for human data can also be found in methods texts of other countries,
such as Canada (Meek et al., 1994) and The Netherlands (Rademaker and Linders, 1994),
international groups such as the International Programme on Chemical Safety (IPCS, 1994;
Meek et al., 2001), other U.S. government organizations such as the Agency for Toxic
Substances and Disease Registry (ATSDR, Pohl and Abadin, 1995) and the Food and Drug
Administration, and independent groups (e.g., Dourson et al., 2001).
Strength of the Perchlorate Database Compared with Human-Based RfDs
We compared the human database for perchlorate with those of other RfDs based on human data
from US EPA’s Integrated Risk Information System (IRIS). We find that the perchlorate human
database is stronger than many on IRIS, as evidenced by estimations of overall confidence, size
Toxicology Excellence for Risk Assessment 3/1/4 2002
of uncertainty factor, and types of available data. Furthermore, we find that US EPA’s proposed
perchlorate RfD based on animal data suggests that it is more toxic than aldicarb (30- fold more
toxic), arsenic (10- fold more toxic), methyl mercury (3- fold more toxic), and warfarin (10-fold
more toxic).
Table 1 shows a comparison of the perchlorate database of human studies in relationship to other
RfDs base on human data found on EPA’s IRIS. Three points of comparison are shown. The
first comparison is that of available human data, listed in Table 1 as clinical, epidemiology, and
occupational. A second point of comparison is the size of the uncertainty factor. A third point of
comparison is the size of confidence levels. These latter two comparisons, however, depend on a
judgment by us that the overall uncertainty factor for perchlorate of 3- fold with these human data
is appropriate, and that the confidence in the RfD for perchlorate based on human data is high.
EPA judges the overall uncertainty factor based on animal data to be 300, and the overall
confidence in the perchlorate RfD to be medium.
A comparison of the available human data of various types for the RfDs shows that perchlorate
has human data in all three categories: clinical, epidemiology, and occupational. This is perhaps
not surprising for a chemical that is both a drug and an environmental contaminant. This same
amount of data is found for only one other human-based RfD, that is barium. In contrast, 23
other human-based RfDs on IRIS have fewer available types of studies.
A comparison of uncertainty factors in the various RfDs sho ws that a proposed human-based
RfD for perchlorate (TERA, 2002)1 has the same uncertainty factor as five other human-based
RfDs; uncertainty factors for five other human-based RfDs are lower; uncertainty factors for 14
human-based RfDs are higher. A comparison of confidence levels in the various RfDs shows
that the perchlorate has the same high confidence rating as 7 other human-based RfDs: cadmium,
fluorine, methyl mercury, nitrate, nitrite, primiphos methyl, and selenium and compounds. The
perchlorate RfD has a higher confidence rating than 17 other human-based RfDs.
Comparison of the Value of EPA’s Proposed Perchlorate RfD to Human-Based RfDs
How does EPA’s proposed RfD for perchlorate of 3 E-5 mg/kg-day compare with RfDs of other
chemicals on IRIS? Our findings show that EPA’s proposed RfD is lower than any other human
based RfD on IRIS, including aldicarb, where the proposed perchlorate RfD is 30- fold lower,
arsenic, where it is 10- fold lower, and methyl mercury where it is 3- fold lower. Table 2 shows
these results. In fact, EPA’s proposed RfD for perchlorate is lower than all but 9 chemicals on
IRIS, only being exceeded in toxicity by aroclor 1254, EPN, heptachlor epoxide, sodium
fuloroacetate, tetra ethyl lead, and white phosphorus as shown in Table 3.
1 Based on a 20% BMDL for iodine uptake inhibition from Greer, 2002 and an uncertainty factor of 3 for
intraspecies variability.
Toxicology Excellence for Risk Assessment 3/1/5 2002
Table 1. Comparison of Perchlorate Human Database with EPA’s RfDs On IRIS
As Of May 2000.2
Chemical
(as on IRIS)
Clinical
Epidemiology
Occupation
Study type for
RfD
UF
RfD
RfD
Confidence
Aldicarb v
v
Human
experimental
gavage
10 1 E-3 Medium
Arsenic,
inorganic
v
Human
epidemio-logy
drinking water
3 3 E-4 Medium
Barium v
v
v
Human
experiment,
epidemio-logical
drinking water
3 7 E-2 Medium
Baygon v
Human
experimental
single dose
100 4 E-3 Medium
Benzoic acid v
v
Human anecdotal
dietary exposure
1 4 E+0 Medium
Cadmium v
v
Human chronic
exposures from a
variety of studies
10 5 E-4 High
Chlorpyrifos v
Human
experimental
capsule
10 3 E-3 Medium
4,6-Dinitro-ocyclohexyl
phenol
v
Human anecdotal
clinical therapy
1000 2 E-3 Low
2,4-
Dinitrophenol
v
Human anecdotal
clinical therapy
1000 2 E-3 Low
Ethephon v
Human
experimental oral
exposure
100 5 E-3 Low
Ethion v
Human
experimental
short term
100 5 E-4 Medium
Fluorine (soluble
fluoride)
v
Human
epidemiology
1 6 E-2 High
Malathion
v
Human
experimental
feeding
10 2 E-2 Medium
Manganese v
Human data of
several types
1 1.4 E-3 Medium
Methylmercury
v
Human
epidemio-logical
poisoning
10 1 E-4 High
2 Availability of data is defined as studies described in EPA’s IRIS RfD file only. Some chemicals are known to
have other data for the inhalation route (e.g., manganese).
Toxicology Excellence for Risk Assessment 3/1/6 2002
Chemical
(as on IRIS)
Clinical
Epidemiology
Occupation
Study type for
RfD
UF
RfD
RfD
Confidence
Molybdenum
v
v
Human
epidemiological
dietary
30 5 E-3 Medium
Nitrate v
v
Human
epidemiology
surveys
1 1.6 E+0 High
Nitrite v
v
Human
epidemio-logy
surveys
1 1 E-1
High
Perchlorate
v
v
v
Epidemiology
Study
3
2 E-3
High3
Pirimiphosmethyl
v
Human 56 day
experimental
feeding
25 1 E-2 High
Selenium and
Compounds
v
Human food and
soil
epidemiology
3 5 E-3 High
Silver v
Human anecdotal
studies
3 5E-3 Low
1,1,2-Trichloro-
1,2,2-
trifluoroethane
v
v
Human
occupation
exposure
10 3E+1 Low
Warfarin
v
v
Human
experimental
100 3E-4 Low
Zinc and
Compounds
v
Human
experimental
3 3E-1 Medium
Toxicology Excellence for Risk Assessment 3/1/7 2002
Table 2. Ratio Of IRIS Human Data RfD To EPA’s Proposed Perchlorate Rat Based RfD3.
IRIS RfD
Type of Human Study Ratio4
Aldicarb experimental gavage 30
Arsenic, inorganic epidemiology drinking water 10
Barium experimental, epidemiological drinking water 2000
Baygon experimental single dose 100
Benzoic acid anecdotal dietary exposure 100,000
Cadmium chronic exposures from a variety of studies 20
Chlorpyrifos experimental capsule 100
Dinitro-o-cyclohexyl phenol anecdotal clinical therapy 70
2,4-Dinitrophenol anecdotal clinical therapy 200
Ethephon experimental oral exposure 200
Ethion experimental short term 20
Fluorine (soluble fluoride) epidemiology 2000
Malathion experimental feeding 700
Manganese data of several types 50
Methylmercury epidemiological poisoning 3
Molybdenum epidemiological dietary 200
Nitrate epidemiology surveys 50,000
Nitrite epidemiology surveys 3000
Perchlorate5 epidemiology study 70
Pirimiphos-methyl 56 day experimental feeding 300
Selenium and Compounds food and soil epidemiology 200
Silver anecdotal studies 200
Trichlorotrifluoroethane occupational exposure 100,000
Warfarin experimental 10
Zinc and Compounds experimental diet supplement 10,000
3 Of 0.00003 mg/kg-day from EPA, 2002
4 Ratio determined by dividing the IRIS RfD by the proposed perchlorate RfD. The value can be interpreted as how
much more toxic perchlorate is than the given chemical on a chronic basis.
5 As Per Toxicology Excellence For Risk Assessment (v. infra)
Toxicology Excellence for Risk Assessment 3/1/8 2002
Table 3. RfDs on IRIS with values equal to or lower than that proposed by
EPA for perchlorate.
Chemical
Value of the RfD (mg/kg-day)
Aldrin
3x10-5
Aroclor 1254
2x10-5
Ethyl p-nitrophenyl phenylphosphorothioate (EPN)
1x10-5
Heptachlor epoxide
1.3x10-5
Merphos
3x10-5
Merphos oxide
3x10-5
Sodium fluoroacetate
2x10-5
Tetraethyl lead
1x10-7
White phosphorus
2x10-5
Toxicology Excellence for Risk Assessment 3/1/9 2002
Human Data Policy
On December 14, 2001 EPA (U.S. EPA, 2001) released its interim policy on the use of thirdparty
studies submitted by regulated entities, and stated its intentions for the National Academy
of Sciences to review this policy. The third-party studies that will be the focus of the Academy
review are those that have not been conducted or funded by a federal agency in compliance with
EPA's Common Rule, or its equivalent. In its press release, EPA indicated "Our paramount
concern in developing our policy on these studies must be protection of human health and
adherence to the most rigorous ethical and scientific standards." … “During the Academy's
consideration of the issues and until a policy is in place, the Agency will not consider or rely on
any such human studies in its regulatory decision making, whether previously or newly
submitted.”
EPA’s perchlorate risk assessment cites this policy as one reason why the human database is not
adequately considered in the development of the RfD. However, it is inappropriate to apply this
policy in the risk assessment for perchlorate for the
following reasons:
· This is not a regulatory decision, it is a scientific assessment. As such it should consider
any valid scientific studies that are available. Policies relating to regulatory action should
be applied at the appropriate regulatory stage.
· The primary clinical study (Greer et al., 2002) was not a 'third party study' as intended in
the policy. The study was designed over a period of one year in discussions among the
EPA, DOD, and the Principal Investigator and sponsor. Its design accounted for the
needs of the DOD for kinetic data for modeling, the PI and lab design constraints and the
EPA's specific needs for the risk assessment. The role of the sponsor was simply to fund
and monitor the study and to provide the data to EPA so this study should not be
considered to be a third part study according to the policy.
· The EPA policy was stimulated by concern about human subject in studies of new
pesticides, i.e., relatively unstudied compounds, and the potential unknown risks of
exposure. In contrast, perchlorate is a well-understood chemical with a well-known
mode of action on the thyroid. The Greer study is primarily looking at inhibition of iodine
uptake in euthyroid, iodine sufficient subjects. Inhibition of iodine uptake for a short
time is not considered an adverse effect in normal people; it is an early precursor of
effects. The highest perchlorate dose used in the study was almost 1000 times lower than
the dose that is currently prescribed for amiodorone induced thyrotoxicosis.
· The data from the Greer study is used by EPA in the development of the human PBPK
model. If the data can be used for kinetic analysis, it should also be used to understand
potential effects.
· Moreover, the study was conducted at the Oregon Health Sciences University (OHSU),
an institution that conducts clinical studies using federal funds. OHSU had a Multiple
Toxicology Excellence for Risk Assessment 3/1/10 2002
Project Assurance, issued by the federal Office for Human Research Protection (OHRP),
during the time of the Greer study (and since March 2001, has had a Federal-Wide
Assurance). These assurances indicate that the OHSU studies are conducted in
compliance with the Common Rule.
The basis of the concern about human studies seems to be related to ethical issues. The design
and conduct of the Greer study has been evaluated for compliance with the Common Rule, the
principles guiding ethical treatment of human studies for the EPA. Moreover, the study was the
subject of a rigorous QA/QC audit, which was directed by EPA and was a condition for
acceptance of the data or its use in the PBPK modeling by EPA. The results of these two
evaluations of the Greer study are presented in the following sections.
Compliance of Greer Study with the Common Rule
TERA evaluated the human study by Dr. Monte Greer (Oregon Health Scie nces University), as
sponsored by The Perchlorate Study Group, to answer the question "Has this human study met
the criteria as established under the Common Rule for the ethical treatment of human subjects?"
The Common Rule, as adopted by the US Environmental Protection Agency (EPA), applies only
to federally funded research involving human subjects. Note that under current US EPA
regulations, this study was not subject to the Common Rule requirements (40 CFR 26).
There are three major requirements of the Common Rule -- review and approval by an
Institutional Review Board (IRB), informed consent, and written assurance by government
agencies of compliance with Common Rule requirements. This independent evaluation of the
Greer human studies has focused on all of these elements in determining whether this study met
the requirements of the Common Rule. Note that the third requirement for written assurance is
not relevant to this particular study, as The Perchlorate Study Group is not a government agency;
however, the Oregon Health Sciences University (OHSU) conducts studies that are federally
funded and during the time of this study OHSU had a Multiple Project Assurance (and since
March 2001, has had a Federal-Wide Assurance), indicating that OHSU operates in compliance
with the Common Rule.
To conduct this review, TERA identified key elements of the Common Rule and then examined
the Greer study documentation (protocol, IRB approval letter/memorandum, IRB Policy and
Procedure Manual, sample consent form, etc.) to determine whether the key elements were
addressed. The following summarizes the findings of this review. A more detailed evaluation is
found in Appendix B, which identifies the key elements of the Common Rule and the
corresponding documentation of the Greer study that indicates compliance with these key
elements.
Review and Approval by Institutional Review Board
The protocol and sample consent form for the Greer study were approved by the IRB on
February 1, 2000, as evidenced by an approval letter. Additionally, in a Memorandum dated
Toxicology Excellence for Risk Assessment 3/1/11 2002
April 12, 2000, the IRB approved a “Project Revision Amendment” to revise the consent form
for the “uptake only” portion of the study. The protocol does not state per se that the study was
conducted in compliance with the Common Rule; however, a review of the OHSU 2000
Institutional Review Board Policy and Procedure Manual
(http://www.ohsu.edu/ra/rso/irb/irbpolicy2000.pdf) and a roster of the IRB from January-June
2000 showed compliance with the Common Rule requirements for IRBs. Additionally, the
OHSU 2000 IRB Policy and Procedure Manual was written to ensure compliance with the
Common Rule requirements as promulgated by the Department of Health and Human Services
(45 CFR 46). For this review, language from the OHSU 2000 IRB Policy and Procedure Manual
was compared with the language in the Common Rule as promulgated by EPA (40 CFR 26) and
found to be nearly identical. A review of the IRB manual and approval letters provides evidence
that this study has met the Common Rule requirement of IRB review and approval (including the
requirements of IRB membership, documentation, and procedures).
Written Informed Consent
Based on a review of the protocol, consent form, and TRS quality assurance audit, this study met
the requirements of informed consent under the Common Rule. The protocol (and also the
OHSU 2000 IRB Policy and Procedure Manual) specifically stated that the study investigators
would obtain written informed consent from each subject prior to commencing the study. This
was verified in the TRS quality assurance audit (i.e., the Protocol Requirements Spreadsheets
and Notes). The audit indicated that each subject had signed a consent form. It also noted that
two of the original consent forms were lost, so these consent forms were resigned by the subjects
after study completion. A review of the consent form approved by the IRB indicates that the
Common Rule requirements for informed consent were followed. For example, the consent form
was written in understandable language; it explained the purpose, procedures and duration of
research; it contained information about risks/benefits of the research, costs and compensation to
subject, confidentiality of records, contact information for questions, consequences of early
withdrawal from study, and legal rights. Most importantly, the consent form specifically stated
that participation “is completely voluntary” and that the subjects “are free to choose not to serve
as a research subject…for any reason.” The protocol stated that, “To further assure informed
consent, at the Preliminary Visit all potential volunteers will be asked to take home the materials
provided and to phone the next day with their decisions concerning participation. Informed
consent will be documented by having the volunteer sign the consent form in front of the
principal investigator.” Based on this information, this study meets the Common Rule
requirement of informed consent.
Written Assurance
Although the requirement for written assurance by government agencies is not relevant to this
particular study, the attached letter (dated February 14, 2002, See Appendix B) to TERA from the
Manager of Research Compliance and Assurance at OHSU states that “OHSU conducts all
research according to the terms of our federal assurance.” The letter also states that during the
time of this study, “OHSU operated under a Multiple Project Assurance [MPA] (M1359)” and
indicated that the IRB at the time of the study was “constituted according to the requirements of
45 CFR 46.” Additionally, the OHSU 2000 IRB Policy and Procedure Manual states, “The
Toxicology Excellence for Risk Assessment 3/1/12 2002
federal Office for Human Research Protection (OHRP) notified OHSU on May 29, 1996 that the
MPA had been approved. The new MPA became effective June 1, 1996 and extends for five
years” (chapter 1, page 1). The MPA details OHSU’s efforts to comply with federal
requirements. Thus during the time of this study, OHSU was operating under a MPA and
therefore, met the written assurance requirement of the Common Rule even though it was not a
requirement for this particular study.
QA/QC Audit of Greer Study
EPA required that the Greer study undergo a rigorous QA/QC audit as a condition for acceptance
of the data or its use in the PBPK modeling. The QA/QC audit was conducted by
Toxicology/Regulatory Services, Inc. (TRS), who submitted a final audit report to Department of
Defense and the Principal Investigator on April 11, 2001. The principal investigator and the
DOD addressed deficiencies identified in the audit report; DOD submitted a consultative letter
addressing the audit on May 10, 2001. The TRS audit report and DOD consultative letter can be
found on EPA’s data CD as document ID# 98977. A summary of the TRS audit procedure is
presented in Appendix B.
Comments below on the TRS audit report of the Greer human study, together with the study
investigators' responses to it, were reviewed by TERA staff member Daniel W. Briggs, R.Ph.,
Ph.D., DABT. Dr. Briggs joined TERA as a Visiting Scientist in the fall of 2001 after devoting
over 25 years as a toxicologist and manager of product safety for the Procter & Gamble
Company. Dr. Briggs has designed and conducted human clinical studies on a variety of
personal care products and their ingredients, using both contract laboratories and university
facilities, and he is experienced in monitoring and auditing these types of studies.
TRS, Inc. has done a thorough job evaluating a number of different areas of the Greer
perchlorate pharmacokinetics and iodine uptake study. Their audit includes an assessment of the
study’s compliance with protocol requirements and the adequacy of supporting documentation,
plus reviews of the data that were collected on thyroid function; on serum and urinary iodine
levels; and serum chemistry, hematology, and urinalysis values.
The audit report identifies issues in all of the areas that were evaluated. The types of errors,
omissions, and protocol deviations listed in the audit report are those that occur commonly in
human clinical studies. This is especially true when the clinical studies are conducted in
university settings where staff personnel generally receive little training in the requirements of
Good Clinical Practices and are oriented more towards scientific research than regulatory
compliance and strict adherence to documentation requirements.
Many of the findings emphasized in the audit relate to the absence or inconsistency of available
documentation related to sample collections. Difficulties in obtaining raw data records to verify
sample identities and sample collection times also were listed as notable shortcomings of the
study. In addition, some of the documentation provided to TRS was in the form of Excel
spreadsheets, raising concerns of data recording and storage vulnerabilities because of
possibilities that the spreadsheets may have undergone alterations without proper tracking and
documentation of changes. Subsequently, these issues were addressed and largely negated when
Toxicology Excellence for Risk Assessment 3/1/13 2002
the investigators clarified the procedures used to transfer raw data from sample labels and lab
slips to a Paradox database. The Excel spreadsheets were not used for data storage but were
prepared at a later date from the Paradox database for the sole purpose of meeting the auditor’s
requests for information.
Other findings in the audit report describe omissions of sample analyses, recording errors, and
discrepancies between the protocol and the study execution. In some cases, further explanation
and clarification from the investigators resolved these issues; in other cases measures were taken
to correct confirmed documentation errors or to perform procedures that were mistakenly
omitted. Details describing how the audit findings were addressed are provided in the
investigators’ point-by-point response to the audit report (Goodman, Previti, and Pino; April 26,
2001). Although some issues identified in the audit report could not be satisfactorily resolved by
further explanation or corrective action, none of these remaining items are judged sufficient to
invalidate this study or to question its scientific credibility.
In the concluding remarks of its audit report, TRS states that the information presented in the
perchlorate study, when combined with the subsequent data corrections and additional
documentation “may permit a scientific reviewer to conclude that the data from this study are
reliable and accurate enough to support the PB/PK modeling project." This conclusion appears
to be justified. The explanatory document (referenced above) prepared in response to the TRS
audit report demonstrates the study investigators intimate familiarity with the key aspects of this
study, suggesting that the study was well-managed overall, even though a number of errors,
omissions, and protocol deviations occurred.
No findings were presented in the TRS audit report that would prevent the Greer study from
being used for risk assessment purposes.
Conclusion
Overall, we disagree with EPA’s conclusions regarding the quality of the human data. The
EPA’s review of the epidemiology studies reflects some misunderstanding of the biological basis
of the neonatal thyroid-screening program, leading to misinterpretation of epidemiological and
statistical data. The EPA’s review includes unsupported speculations regarding sources of
potential confounding that leads to minimal use of important data (Appendix A).
Rather, we find that the perchlorate human database is stronger than many on IRIS, as evidenced
by estimations of ove rall confidence, size of uncertainty factor, and types of available data.
Furthermore, we find that US EPA’s proposed perchlorate RfD based on animal data suggests
that it is more toxic than aldicarb (30- fold more toxic), arsenic (10- fold more toxic), methyl
mercury (3-fold more toxic), and warfarin (10-fold more toxic). However, these conclusions are
not supported by the human data, which consistently show no effect associated with perchlorate
exposure.
We conclude that the Greer study meets the three major requirements of the Common Rule --
review and approval by an Institutional Review Board (IRB), informed consent, and written
Toxicology Excellence for Risk Assessment 3/1/14 2002
assurance by government agencies of compliance with Common Rule requirements. A review of
the IRB manual and approval letters provides evidence that this study has met the Common Rule
requirement of IRB review and approval (including the requirements of IRB membership,
documentation, and procedures). Based on a review of the protocol, consent form, and TRS
quality assurance audit, this study met the requirements of informed consent under the Common
Rule. During the time of this study, “OHSU operated under a Multiple Project Assurance
[MPA] (M1359)” and indicated that the IRB at the time of the study was “constituted according
to the requirements of 45 CFR 46” and therefore, met the written assurance requirement of the
Common Rule even though it was not a requirement for this particular study.
Finally, a thorough QA/QC audit was conducted on the Greer study. No findings were presented
in the TRS audit report that would prevent the Greer study from being used for risk assessment
purposes. The response to the TRS audit report demonstrates the study investigators intimate
familiarity with the key aspects of this study, suggesting that the study was well-managed
overall, even though a number of errors, omissions, and protocol deviations occurred.
Toxicology Excellence for Risk Assessment 3/1/15 2002
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Answer 2

Um if you are raising it to powers then the problem is a little more complicated but for what you have typed in your problem would go as follows:
2(2-e)-(-3)(e-4)=-3(e-4)
4-2e+3e-12=-3e+12
e-8=-3e+12
4e=20
e=5

Answer 3

2(2-e)-(-3)(e-4)=-3e-4)
4 - 2e + 3e - 12 = -3e - 4
-8 + e = -3e - 4
4e = 4
e = 1

There are no exponents in this problem.

Answer 4

e-1=0

Answer 5

2(2-e)-(-3)(e-4)
(4-2e)-(-3e+12)= -3e-4
(4-2e)+(3e-12)= -3e-4
thats as far as im going... babe if u cant solve problems THIS simple your best bet is to get out of the class...

Answer 6

4-2e+3e+12
=4+12+e
=e+16

don't understand what the point of that was... was i right?

Answer 7

You may want to rewrite your question a little more clearly. You have a ) on the right side, but no (.

Also, all of he e's are to the first power, the way you have it written. If you mean to write "e to the negative third power", type e^-3

Answer 8

you mean 2^(2-e) - (-3)^(e-4) = -3^(e-4) If this is the case I believe your next move is
2^(2-e) = -6^(e-4)
I don't remember what to do from there boss

Answer 9

properly i'm no longer for confident of the value of the variables yet al i will help with is which you multiply what vet the value of the variable is thru the variety. Eg- 4•value of variable. Sorry... no longer a lot of a help

Answer 10

4-2e-(-3)(e-4)=-3e-4
4-2e-(-3e)+12=-3e-4
4-2e+3e+12=-3e-4
e+16=-3e-4
4e+10=-4
4e=-20
e=-5

Answer 11

Do your own homework I already graduated!