WordNet

travel or traverse (a distance); "This car does 150 miles per hour"; "We did 6 miles on our hike every day"
the syllable naming the first (tonic) note of any major scale in solmization (同)doh, ut
proceed or get along; "How is she doing in her new job?"; "How are you making out in graduate school?"; "Hes come a long way" (同)fare, make_out, come, get along
create or design, often in a certain way; "Do my room in blue"; "I did this piece in wood to express my love for the forest" (同)make
carry on or function; "We could do with a little more help around here" (同)manage
get (something) done; "I did my job" (同)perform
refer to; "he referenced his colleagues work" (同)cite
the act of referring or consulting; "reference to an encyclopedia produced the answer" (同)consultation
the most direct or specific meaning of a word or expression; the class of objects that an expression refers to; "the extension of `satellite of Mars is the set containing only Demos and Phobos" (同)denotation, extension
a publication (or a passage from a publication) that is referred to; "he carried an armful of references back to his desk"; "he spent hours looking for the source of that quotation" (同)source
the relation between a word or phrase and the object or idea it refers to; "he argued that reference is a consequence of conditioned reflexes"
treat with an agent; add (an agent) to; "The ray dosed the paint"
the quantity of an active agent (substance or radiation) taken in or absorbed at any one time (同)dosage
a measured portion of medicine taken at any one time (同)dosage
supported with written references or citations; "a carefully referenced biography"
treated with some kind of application; "a mustache dosed with bear grease"

PrepTutorEJDIC

《疑問文・否定文を作る》 / 《否定命令文を作る》 / 《助動詞とbe動詞のどちらも含まない文に用いて付加疑問を作る》 / 《強意語として》 / 《文》《助動詞とbe動詞のどちらも含まない文に用いて倒置文を作る》 / 《あいづちを打つ場合に》 / 《先行する動詞またはそれを含む述部の代用》 / 《so,nor,neitherで始まる簡略文で》 / …‘を'『する』,行う,果たす / 《通例have done,時にbe doneの形で》…‘を'『終える』,済ませる / …‘を'作る,作り出す / …‘を'『処理する』,整える,片付ける / 〈学課〉‘を'『勉強する』,専攻する / 〈利益・害など〉‘を'与える,もたらす / 〈人〉‘に'『役立つ』,用が足りる(serve) / …の速度で進む,距離を行く / …‘を'見物する / 〈劇〉‘を'上演する;…‘の'役を演じる / …の役目(仕事)をする / 《おもに英》…‘を'だます,かつぐ / 《話》…をへとへとにさせる / 『する』;活動する / 《通例have done,時にbe doneの形で》(…を)『終える』,済ます《+『with』+『名』》 / 〈事が〉『運ぶ』;〈人が〉暮らしていく,健康である / 〈物が〉(…に)『間に合う』,十分である;〈人が〉(…に)役に立つ,向く《+『for』+『名』》 / 《複数形で》すべきこと / 〈C〉《おもに英》大宴会,大パーティー / 〈C〉《英話》詐欺,ぺてん
ド(全音階の第1音)
〈U〉(…へ)『言及すること』,(…の)話に触れること《+『to』+『名』》;〈C〉言及した事柄 / 〈U〉(…を)『参照すること』,参考《+『to』+『名』》;〈C〉(本などの)出典,参考書;(出典などの)注記 / 〈C〉(人物・才能などの)証明書;身元保証人,照会先
(おもに飲み薬1回分の)『服用量』 / (痛いこと・いやなことの)1回分,一定量 / (人などが受ける放射線の)線量 / 性病 / (…を)…‘に'投薬する,服用させる《+『名』+『with』+『名』》

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/10/15 00:09:01」(JST)

wiki en

A reference dose is the United States Environmental Protection Agency's maximum acceptable oral dose of a toxic substance. Reference doses are most commonly determined for pesticides. The EPA defines an oral reference dose (abbreviated RfD) as:

[A]n estimate, with uncertainty spanning perhaps an order of magnitude, of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.^[1]

Regulatory status

Unlike National Ambient Air Quality Standards, RfDs are not enforceable standards. Instead, the EPA uses RfDs as risk assessment benchmarks and tries to set other regulations so that people are not exposed to chemicals in amounts that exceed RfDs. According to the EPA, "[a]n aggregate daily exposure to a [chemical] at or below the RfD (expressed as 100 percent or less of the RfD) is generally considered acceptable by EPA."^[2] For example, the EPA set an acute RfD for children of 0.0015 mg/kg/day for the organochlorine insecticide endosulfan, based on neurological effects observed in test animals. The EPA then looked at dietary exposure to endosulfan, and found that for the most exposed 0.1% of children age 1–6, their daily consumption of the endosulfan exceeded this RfD. To remedy this, the EPA revoked the use of endosulfan on the crops that contributed the most to exposure of children: certain beans, peas, spinach, and grapes.^[3]

Types

Reference doses are chemical-specific, i.e. the EPA determines a unique reference dose for every substance it evaluates. Often separate acute and chronic RfDs are determined for the same substance. Reference doses are specific to dietary exposure. When assessing inhalation exposure, EPA uses "reference concentrations" (RfCs), instead of RfDs. Note that RfDs apply only to non-cancer effects. When evaluating carcinogenic effects, the EPA uses the Q₁* method.

Determination

RfDs are usually derived from animal studies. Animals (typically rats) are dosed with varying amounts of the substance in question, and the largest dose at which no effects are observed is identified. This dose level is called the "No observable effect level," or NOEL. To account for the fact that humans may be more or less sensitive than the test animal, a 10-fold uncertainty factor is usually applied to the NOEL. This uncertainty factor is called the "interspecies uncertainty factor" or Uf_inter. An additional 10-fold uncertainty factor, the "intraspecies uncertainty factor" or Uf_intra, is usually applied to account for the fact that some humans may be substantially more sensitive to the effects of substances than others. Additional uncertainty factors may also be applied. In general:

Frequently, a "no-observed-adverse-effect level" or NOAEL is used in place of a NOEL. If adverse effects are observed at all dose levels tested, then the smallest dose tested, the "lowest-observed-adverse-effect level" or LOAEL, is used to calculate the RfD. An additional uncertainty factor usually applied in these cases, since the NOAEL, by definition, would be lower than the LOAEL had it been observed. If studies using human subjects are used to determine a RfD, then the interspecies uncertainty factor can be reduced to 1, but generally the 10-fold intraspecies uncertainty factor is retained. Such studies are rare.

Example

As an example, consider the following determination of the RfD for the insecticide chlorpyrifos, adapted from the EPA's Interim Reregistration Eligibility Decision for chlorpyrifos.^[4]

The EPA determined the acute RfD to be 0.005 mg/kg/day based on a study in which male rats were administered a one-time dose of chlorpyrifos and blood cholinesterase activity was monitored. Cholinesterase inhibition was observed at all dose levels tested, the lowest of which was 1.5 mg/kg. This level was thus identified at the lowest observed adverse effect level (LOAEL). A NOAEL of 0.5 mg/kg was estimated by dividing the LOAEL by a three-fold uncertainty factor. The NOAEL was then divided by the standard 10-fold inter- and 10-fold intraspecies uncertainty factors to arrive at the RfD of 0.005 mg/kg/day. Other studies showed that fetuses and children are even more sensitive to chlorpyrifos than adults, so the EPA applies an additional ten-fold uncertainty factor to protect that subpopulation. A RfD that has been divided by an additional uncertainty factor that only applies to certain populations is called a "population adjusted dose" or PAD. For chlorpyrifos, the acute PAD (or "aPAD") is thus 5×10⁻⁴ mg/kg/day, and it applies to infants, children, and women who are breast feeding.

The EPA also determined a chronic RfD for chlorpyrifos exposure based on studies in which animals were administered low doses of the pesticide for two years. Cholinesterase inhibition was observed at all dose levels tested, and a NOAEL of 0.03 mg/kg/day estimated by dividing a LOAEL of 0.3 mg/kg/day by an uncertainty factor of 10. As with the acute RfD, the chronic RfD of 3×10⁻⁴ mg/kg/day was determined by dividing this NOAEL by the inter- and intraspecies uncertainty factors. The chronic PAD ("cPAD") of 3×10⁻⁵ mg/kg/day was determined by applying an additional 10-fold uncertainty factor to account for the increased susceptibility of infants and children. Like the aPAD, this cPAD applies to infants, children, and breast feeding women.

Consensus

Because the RfD assumes "a dose below which no adverse noncarcinogenic health effects should result from a lifetime of exposure",^[5] the critical step in all chemical risk and regulatory threshold calculations is dependent upon a properly derived dose at which no observed adverse effects (NOAEL) were seen which is then divided by an uncertainty factor that considers inadequacies of the study, animal-to-human extrapolation, sensitive sub-populations, and inadequacies of the database. The RfD that is derived is not always agreed upon. Some may believe it to be overly protective while others may contend that it is not adequately protective of human health.

For example, the EPA completed its draft toxicological review of perchlorate in 2002 and proposed an RfD of 0.00003 milligrams per kilogram per day (mg/kg/day) based primarily on studies that identified neurodevelopmental deficits in rat pups. These deficits were linked to maternal exposure to perchlorate. Subsequently, the National Academy of Science (NAS) reviewed the health implications of perchlorate, and in 2005 proposed an alternative reference dose of 0.0007 mg/kg/day based primarily on a 2002 study by Greer et al.^[6] During that study, 37 human subjects were split into four exposure groups exposed to 0.007 (7 subjects), 0.02 (10 subjects), 0.1 (10 subjects), and 0.5 (10 subjects) mg/kg/day. Significant decreases in iodide uptake were found in the three highest exposure groups. Iodide uptake was not significantly reduced in the lowest exposed group, but four of the seven subjects in this group experienced inhibited iodide uptake. The RfD proposed by NAS was accepted by EPA and added to its integrated risk information system (IRIS) in 2005.

Ginsberg and Rice, in a commentary submitted to the journal Environmental Health Perspectives (EHP), argued that the 2005 NAS RfD was not protective of human health based on the following:

The NAS report described the level of lowest exposure from Greer et al as a NOEL. However, there was actually an effect at that level although not statistically significant largely due to small size of study population (four of seven subjects showed a slight decrease in iodide uptake).
Reduced iodide uptake was not considered to be an adverse effect. However, it is a precursor to an adverse effect (hypothyroidism). Therefore, additional safety factors, they argued, are necessary when extrapolating from the point of departure to the RfD.
Consideration of data uncertainty was insufficient because the Greer, et al. study reflected only a 14-day exposure to healthy adults and no additional safety factors were considered to protect sensitive subpopulations. For example, the potential for greater toxicity to breastfeeding newborns was not considered.

Although there has generally been consensus with the Greer et al study, there is not consensus with regard to developing a perchlorate RfD. One of the key differences results from how the point of departure is viewed (i.e., NOEL or LOAEL), or whether a benchmark dose should be used to derive the RfD. Defining the point of departure as a NOEL or LOAEL has implications when it comes to applying appropriate safety factors to the point of departure to derive the RfD.^[7]

References

^ IRIS Glossary[1]
^ Reregistration Eligibility Decision for 1,3-Dichloropropene
^ Reregistration Eliligibility Decision for Endosulfan
^ Interim Reregistration Eligibility Decision for Chlorpyrifos
^ http://www.epa.gov/ogwdw/uic/class5/pdf/study_uic-class5_classvstudy_mcl-ha_appd.pdf
^ Greer M A, Goodman G, Pleus R C, and S E Greer. (2002) Health Effects Assessment for Environmental Perchlorate Contamination: The Dose Response for Inhibition of Thyroidal Radioiodine Uptake in Humans. Environmental Health Perspectives (110)9: 927-37.
^ http://www.epa.gov/region10/pdf/sites/euclid/eroad-perchlorate-memo-071307.pdf

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