Oxydemeton-methyl

G. Abdollahi , S. Mostafalou , in Encyclopedia of Toxicology (Tertiary Edition), 2014

Creature

The no observed agin upshot level (NOAEL) for oxydemeton-methyl in rats has been determined to exist 0.027 mg kg −1 day−ane in 3-month feeding studies. The results of these studies indicate symptoms such as weight loss, loss of condition, skin inflammation, ulceration, and changes in plasma enzymes and proteins. The NOAEL and lowest observed adverse effect level (LOAEL) values for systemic toxicity in mice administered oxydemeton-methyl orally for 21 months were adamant as 0.five and ii.iii mg kg−1 24-hour interval−ane, respectively. Weight loss, convulsions, and cytoplasmic vacuolation of epididymides in male animals were seen. In another chronic study, oxydemeton-methyl was administered to dogs for 12 months and based on the results, cholinesterase NOAEL and LOAEL were found to be 0.125 and 0.0125 mg kg−1 twenty-four hour period−i.

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Benchmark Dose

M.A. Rezvanfar , in Encyclopedia of Toxicology (3rd Edition), 2014

Characteristics of the BMD Approach

Because of several limitations and some bug associated with using the NOAEL and to motility away from compulsory lethal dose 50% (LDfifty) conclusion, the benchmark concept has been introduced every bit an alternative approach in risk assessment and has been developed and implemented past take a chance assessors to gauge RfDs and RfCs. The BMD concept was introduced by Crump in 1984 and has been presented as a methodological improvement in the field of risk assessment by defining a concentration between the NOAEL and LOAEL. To date, the BMD method has generally been used by authorities, such equally the US EPA and consultants in the The states; research specifically related to this approach has been performed at only a few institutions in Europe. Practical and theoretical knowledge of the method is express.

The European Chemicals Bureau stated that BMD ''… tin can be used in parallel or as an alternative when at that place is no reliable NOAEL." Like statements have been made by other organizations: the Scientific Committee of the European Food Safety Authority (EFSA) 'strongly encourage' all panels and units to adopt the BMD arroyo. Also the Globe Wellness Arrangement's International Panel for Chemical Safety (IPCS) state that BMD ''… tin be considered a more than sophisticated or robust alternative to NOAEL." Even stronger recommendations are fabricated by the U.s. National University Committee for Acute Exposure Guidance Levels, declaring that BMD should be the 'preferred arroyo.' This approach can exist used quite extensively in developmental and reproductive toxicity studies besides as cancer risk assessment. Quantal data is ideally suited for BMD modeling.

The BMD arroyo was developed to better define the POD in the ciphering of the safe dose to overcome the shortcomings of using NOAELs or LOAELs (Tables i and ii). Using the NOAEL approach to approximate adequate homo exposure values such equally RfDs and RfCs has several limitations: (one) it must be one of the tested experimental doses, so it depends on the study pattern and once this dose is identified, the rest of the dose–response curve is ignored; (2) it does not account for variability in the estimate of the dose–response. In essence, the NOAEL is very sensitive to sample size and at that place tin as well exist loftier variability among experiments; (three) it does not business relationship for the slope of the dose–response curve; and (4) information technology cannot be applied when at that place is no NOAEL, except through the application of an uncertainty factor when an LOAEL is used.

Table i. The major characteristics of BMD approach

1.

The magnitude of an effect considered adverse is based on toxicology rather than statistics
2.

Differences in sensitivity betwixt two information sets may be recognized with BMD
3.

BMD gives more detailed data about the dose–response relationship compared with NOAEL
4.

BMD can be combined with probabilistic exposure analyses
5.

BMD can exist used to develop relative potency values used for run a risk assessment of mixtures
half-dozen.

A BMD can be calculated from experiments defective an NOAEL and there is thus no need for complementary studies
7.

All doses and the slope of the curve influence the BMD; this brings actress power to the statistical evaluation compared with the NOAEL arroyo, which might exist used to lower the number of animals used
8.

The BMD is non restricted to the experimental doses; information technology is therefore possible to perform studies with fewer animals in some dose groups
nine.

In dissimilarity to the NOAEL, the confidence interval effectually BMD can be calculated, giving additional information for risk managers. The incitement for increasing the number of animals will be stronger with the BMD compared with NOAEL since a narrow confidence interval (i.due east., higher BMDL) will pb to a higher POD compared with the NOAEL arroyo, which will always be lower with increasing numbers

Table 2. Advantages and limitations of the NOAEL and BMD methods

BMD advantages NOAEL limitations
Not express to experimental doses Highly dependent on dose choice
Less dependent on dose spacing Highly dependent on sample size
Appropriately accounts for variability and doubt resulting from study quality Does not account for variability and uncertainty in the experimental results (e.g., does not account for study quality appropriately)
Takes into account the shape of the dose–response curve and other related data Dose–response information (e.grand., shape of dose–response curve) not taken into account
Corresponds to a consistent response level and can be used to compare results across chemicals and studies Does not correspond to consistent response levels for comparisons beyond studies
Flexibility in determining biologically meaning rates An LOAEL cannot exist used to derive an NOAEL
BMD Limitations NOAEL Advantages
Ability to estimate BMD may be limited past the format of the data presented Tin be used when data are non amenable to BMD modeling
Time consuming Piece of cake to derive
More complicated controlling process Has been the standard method for deriving a POD for decades (e.g., is familiar to most risk assessors)

Compared with the NOAEL approach, the BMD arroyo provides five major advantages:

1.

It is not as sensitive to dose choice. All the experimental information are used to construct the dose–response curve meaning that the BMD is based on data from the entire dose–response curve for the critical effect, rather than only from the unmarried dose (e.grand., NOAEL). Therefore, the BMD reflects the gradient of the dose–response curve.

two.

Information technology is less sensitive to sample size compared with the NOAEL approach, meaning that the BMD arroyo treats sample size accordingly when the lower confidence limit on the BMD (i.due east., BMDL) is used. For example, the smaller the sample, the larger the doubt associated with the BMD estimates and the lower the confidence limits (all else being equal). Therefore, data with lower statistical ability result in lower BMDLs (making their use wellness protective), and improve experiments with more statistical power are rewarded with higher BMDLs.

3.

The BMDL is not constrained to being one of the experimental doses, and calculation of the BMDL allows for interpretation of an NOAEL surrogate when only an LOAEL is available. In addition, the dose-independent BMDL too facilitates comparing of toxicity potencies across chemicals or end points.

4.

The BMD approach can be useful when the dose spacing in a written report is such that the LOAEL is much larger than the NOAEL. Thus, any good study can exist used, fifty-fifty in the absence of an NOAEL, as long as sufficient and appropriate dose–response data are provided so that the dose corresponding to the BMR can exist estimated.

5.

The method represents a single methodology that can exist practical to cancer and noncancer end points. It may also be possible to apply fewer animals in testing.

Despite the superiority of BMD over the NOAEL, there are a number of reasons for the connected use of the NOAEL equally the gold standard. The BMD method is a more advanced arroyo and competence in the area is limited. Many toxicologists and risk assessors are not currently conversant with BMD and notice it difficult to empathise. Moreover, there is no full general agreement and international harmonization regarding the definition of BMDL and software standards. In add-on, another important factor limiting the apply of BMD is that disquisitional studies are oftentimes conducted with a number of doses less than optimal for BMD analysis, therefore, with few dose groups, the adventure of missing the relevant response becomes larger.

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From Hazard to Risk – Assessing the Risk

Charlotte Bernhard Madsen , ... Joseph L. Baumert , in Risk Management for Food Allergy, 2014

Probabilistic Approach

Equally the NOAEL and BMD approaches are non conclusive in this instance, a probabilistic adventure assessment of 0.25   ppm peanut protein in lemonade should be run. The model uses consumption data for lemonade from the 2003–2008 United States National Health and Nutrition Examination Survey. Intake data were conservatively based on a per eating occasion basis, and an estimated 5.7% of the Us population consumes lemonade. The peanut allergic thresholds used in the probabilistic risk assessment were those used to derive the suggested Reference Dose for peanut in chapter 5. From the inputs above nosotros can estimate that the risk of an objective reaction in the peanut allergic persons who drink lemonade is 0.iii%. So if 1,000 representative peanut allergic individuals were to consume the contaminated lemonade, a full of three reactions would exist predicted. But as only 5.7% of the US population drinks lemonade the risk of a reaction in the peanut allergic population as a whole is 0.018%. Further assay of the predicted reactions in the simulations indicate that 5.8% of the predicted reactors had a threshold over the proposed Reference Dose and fell within the range of observed clinical thresholds (Figure 6.iii). As shown in the figure, over 70% of the predicted reactors had thresholds below the most sensitive LOAEL recorded in clinical Double Blind Placebo Controlled Food Challenges (DBPCFCs). Again, due to the asymptotic nature of the distributions, the simulation is predicting a pregnant proportion of reactions in individuals who would have thresholds below the near sensitive peanut allergic individuals in the clinical threshold data fix. In improver, the individuals who would be predicted to react in the simulation would need to consume larger than boilerplate amounts of lemonade in a single eating occasion. Thus, the iii predicted reactions out of 1,000 allergic users would not be expected.

FIGURE 6.3. The histogram illustrates the predicted threshold values of peanut allergic individuals predicted to have a reaction in the user population. The histogram results from the repeated sampling of pairs of values from the peanut dose distribution and the distribution of peanut exposure based on consumption of the product (lemonade containing a flavor carrier contaminated with peanut) and illustrates the proportion of reactions attributable to a particular threshold level. The most sensitive LOAEL from DBPCFCs and the Reference Dose for peanut are indicated. Reactions occurring over the Reference Dose appear in ruby-red.

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Adventure Assessment, Environmental/Occupational

D.Chiliad. Hassenzahl , A.K. Finkel , in International Encyclopedia of Public Health, 2008

Toxicology for take chances assessment

Toxicology involves intentional exposure of individuals (typically animals, rarely but occasionally humans) or parts of organisms (cells, tissue cultures) to controlled amounts or concentrations of potentially harmful agents. As such, toxicology can provide highly specific information about the effects of unmarried agents at concentrations that are determined precisely by the investigators, as opposed to epidemiology, where more often than not the exposures have already occurred and must exist estimated retrospectively. Animal testing allows researchers to observe furnishings over multiple generations as well equally different stages of affliction or injury.

Toxicological studies, still, have several disadvantages. Laboratory exposure levels are typically considerably higher than those experienced in the general environment, although they may in some cases not exceed concentrations actually encountered in the workplace. Therefore, estimates associated with lower-dose effects crave extrapolation. Extrapolation can exist highly contentious, especially over the question of thresholds. Figure 2 depicts four possible examples of extrapolation to a low dose from a hypothetical one-exposure animal written report.

Figure ii. Four possible dose–response extrapolations associated with a toxicological study.

Additional uncertainties ascend from using toxicological studies. Showtime, while animals serve every bit proxies for humans, they are not entirely analogous. Second, dosing frequency in toxicological studies is probable to differ from those in exposures of business organisation. Animal test doses for chronic outcomes are oft artificially regular, using a single exposure route. Third, such tests typically cover only the healthy adult fraction of the creature's life, excluding the first 12   weeks when the brute might be specially susceptible and sacrificing the animals several months earlier they might otherwise succumb to old age. In effect, therefore, we test laboratory animals from the time they are 'toddlers' to 'retirement historic period,' and thereby acquire little about the risks to human infants and octogenarians. Fourth, while toxicology allows specificity through controlling parameters other than dose (including, for instance, other chemicals, nutrient, ambient temperature, feeding times, space resource allotment, and lighting), this artificial control omits possible amplifying or offsetting effects of multiple agent exposures.

Risk assessors use toxicological data (and sometimes epidemiological information) to summate risks in two substantially different means: To derive a dose–response human relationship down to a very low dose (typically the goal when cancer is the endpoint), or to decide a safe dose for chronic non-cancer endpoints.

An assumed or derived continuous (often linear) dose–response function can be used to relate exposure to take chances beyond a range of exposures. This arroyo is most often applied to cancer risks associated with chemical or physical agents and results in probabilistic estimates. Even in cases where dose–response is not thought to be linear, a linear approximation is often used for low dose levels. The assumption of depression-dose linearity has a substantial foundation in both theory and show, although at very low doses, finding statistically significant evidence supporting linearity can be hard (Peto et al., 1991). Crawford and Wilson (1996) observed that low-dose linearity can be expected for both cancer and not-cancer endpoints. Likewise, while linear functions strictly imply some non-cypher excess risk fifty-fifty at infinitesimal dose, in exercise EPA does not extrapolate more than 2–5 orders of magnitude below the substantial doses administered in animal bioassays. In other words, the true dose–response part may be nonlinear below ecology levels, just that would be irrelevant to take chances estimation for human being health.

Doses are often expressed in terms of mass of agent per unit of time, normalized to torso weight and time, for example mg/24-hour interval. Alternatively, continuous airborne exposure is typically given in terms of concentration in the air: Respiration rate and trunk weight can exist used to catechumen this to mass per unit of fourth dimension. An instance of a dose–response function is provided in Figure three . Dose (exposure) is depicted on the horizontal axis and response on the vertical centrality. Typically, response is in units of probability, ranging from 0 to 1. Alternatively, response can exist in absolute terms, such equally number of affected individuals or total number of tumors.

Figure 3. Simplified linear dose–response relationship. Note that since all animals have a natural background charge per unit of cancer, the response (y-axis) is in excess of that background.

Potency, then, is expressed in terms of increased adventure per unit dose. With a linear assumption for the dose–response role at concentrations of concern, this allows a elementary calculation of risk every bit lifetime cancer probability (LCP) (eqn [3]):

[3] LCP Dose = q × dose

where q is empirically derived (for detailed derivation, run across Kammen and Hassenzahl (1999), Cox (1995), or Gratt (1996)). Since LCP is a unitless probability, q has units that are the inverse of dose, e.thou. (mg/kgBW/day)–1. q may likewise be referred to as the unit risk factor.

Converting high-dose animal studies to exposures associated with human responses of business concern (typically around ane in 10   000 to ane in 1   000   000 in environmental settings and every bit high equally 1 in 100 for occupational settings) requires several steps. Beginning, animate being doses must be converted to comparable human doses. Second, a man-health conservative assumption is often fabricated, for example, an upper 95th percentile response associated with each dose or an upper 95th percentile response associated with the ready of doses. Tertiary, some theoretical or practical assumption nigh the dose–response relationship is fabricated; often this is simplified to linear extrapolation from the smallest dose. Finally, authorisation is calculated every bit the slope of this line, through some background expectation of response (no response, lowest observed response, or some other value) at cipher dose. In one case potency is established, the estimated LCP associated with whatsoever dose can be easily calculated. Alternatively, a dose associated with some LCP of business organisation (e.chiliad., i in ten   000) can be calculated by dividing that LCP by say-so.

The second common approach to computing risk from toxicological data assumes some threshold dose level below which adverse effects are not expected. The U.S. EPA establishes a reference dose (RfD) for various chemicals, which is used as a benchmark for regulations involving the chemical. The RfD is defined every bit "an gauge, with uncertainty spanning perhaps an order of magnitude, of a daily oral exposure to the homo population (including sensitive subgroups) that is likely to exist without an appreciable chance of deleterious effects during a lifetime" (Environmental Protection Agency, 2007). In other regulatory settings, the related idea of safe doses – or doses at which agin effects are non expected in humans – is used, for example, the acceptable daily intake (ADI) used at the FDA.

The RfD or other safe dose usually begins with some critical observation, such as the no observed effect level (NOEL), no observed adverse effect level (NOAEL), everyman observed consequence level (LOEL), or a benchmark dose associated with a item probability of response in the population ( Rhomberg, 2004). In guild to translate this brute-based reference bespeak into a human reference point, several adjustment factors must exist introduced, to account for issues such as statistical certainty and quality of data, interspecies variation, intraspecies variation, multigenerational effects, and apply of LOEL as opposed to NOEL. Individual prophylactic factors (EPA calls these dubiousness factors (UFs), even though they are meant to arrange the beast NOAEL or LOAEL to a human being dose with a margin of safety and practice not specifically relate to the amount of uncertainty in the aligning) typically take the values 1, 3, or x. A safe dose (RfD, ADI or other) then, may be calculated as in eqn [4]:

[4] RfDorADI = Experimental Dose / UF

Here, Experimental Dose is the relevant dose from the empirical study (due east.g., NOEL, LOAEL) and UF = ΠUF(1…n), where UFi are the diverse uncertainty factor components. For the EPA, x   ≤   UF   ≤   3000.

Current controversies regarding the NOAEL-plus-uncertainty-factors arroyo heart on three problems:

•

whether the private rubber factors are too big (meet, e.g., Dourson et al., 1996) or too pocket-sized (see, due east.thousand., Hattis et al., 1999) to serve their intended purpose of estimating a dose that provides a reasonable certainty of no harm;

•

whether the NOAEL itself is a prophylactic dose in the test animals or merely ane that does not significantly elevate disease rates above background;

•

whether the paradigm itself is valid or whether instead assessors should strive to estimate continuous dose–response relationships for non-carcinogens as they exercise for carcinogens (see, eastward.g., Baird et al., 1996).

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Silicones

J.H. Fain , S. Gad , in Encyclopedia of Toxicology (Third Edition), 2014

Animals

In rats, a no observed adverse effect level of 1000  mg   kg− i twenty-four hours−1 has been reported, although no significant chronic toxic furnishings have been reported for the bulk of siloxane materials. Eye irritation following several months of daily ingestion of PDMS-containing food has been the most frequently reported adverse effect. Even in pyrolysis tests, mice exposed to degradant gases showed few signs of toxicity due to a variety of silicon polymers. Smaller cyclic polydimethylsiloxanes (specially D3 and D4) are toxic and can lead to production of antinuclear antibodies.

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Role of risk assay and risk communication in nutrient safety management

D.P. Attrey , in Food Safety in the 21st Century, 2017

five.five.1 Safety Assessment as Risk Assessment

The well-known no-observed-adverse-effect-level/safety factor-uncertainty factor (NOAEL/SF-UF) process has long been used to empathize and regulate exposure to any potentially toxic substance. In controlled exposures, substance has no apparent or observable agin wellness effect. Awarding of SF-UF(s), which typically composed of multiples of 10, produces a level of exposure that may lead to evolution of a regulatory standard such as an Acceptable Daily Intake (ADI), a Provisional Tolerable Weekly Intake (PTWI), Reference Dose (RfD), or Minimal Risk Level (MRL). Although information technology was first introduced by United states of america Nutrient and Drug Assistants for the purpose of regulating food additives, NOAEL/SF-UF procedure is now widely used for other potentially toxic substances also. A key characteristic of NOAEL/SF- UF process is that at no betoken does it yield a quantitative prediction of harm. NOAEL/SF-UF process is intended to constitute safety. In a legal sense, procedure often defines what the word "rubber" means for the potentially toxic substance (Carrington and Bolger, 2000).

Uncertainty remains an important function of condom cess. Information technology is usually understood that magnitude of dubiety increases with degree of doubtfulness, since NAOEL/SF-UF procedure is designed to establish "certainty," that a substance is safe (e.g., a nutrient condiment). However, in a safety assessment there is no effort to state either how great the dubiety is or precisely what the impact of the uncertainty on take chances management decisions.

Carrington and Bolger (2000) have observed that ADI concept is flawed considering in do, the ADI is viewed every bit an "adequate" level of exposure, and, by inference, any exposure greater than ADI is seen as "unacceptable." ADI was the basis for a regulation on food additives. Information technology was used to calculate how much of the additive could be added to food, with acceptance of the agency as a thing of policy. In order to bargain with this "problem," the ADI was renamed as "RfD."

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General Considerations

Daphne B. Moffett , ... Bruce A. Fowler , in Handbook on the Toxicology of Metals (4th Edition), 2015

5.2 Benchmark Dose Approach

Some of the shortcomings of the NOAEL approach can be rectified through the use of the benchmark approach; this is now gaining attention as an culling. A BMD is defined every bit the statistical lower confidence limit of the dose producing a predetermined level of change in an agin response compared with the response in untreated animals [the criterion response (BMR)] (Crump, 1995). It is determined by modeling a dose-response bend in the region of the dose-response relationship where biologically appreciable data are available. The BMR is mostly set near the lower limit of responses that can be measured directly in animal experiments of typical size. The BMD method does non extrapolate to doses far below the experimental range. There are multiple advantages to using the BMD in identify of NOAEL. First, the BMD is not constrained to using only one experimental dose, dissimilar the NOAEL approach. 2d, the BMD accounts for variability in the data and incorporates response data from groups other than the experimental study determining the NOAEL. Finally, a BMD can be defined even when all experimentally observed responses would exist considered effect levels (i.due east. there is no NOAEL), and thus tin can avoid application of additional uncertainty factors. Nonetheless, current guidelines for the pattern of toxicity tests are based on assessing a NOAEL. It has been suggested that the current study design may not be optimal for assessing a BMD. To further investigate this, three simulation studies in which a big number of designs were compared, focusing on continuous endpoints were performed (Crump, 1995). Iv fictitious endpoints were considered: their underlying dose-response curves had a linear, sublinear, supralinear, or sigmoidal shape. In each simulation run the BMD was derived from a model fitted to the generated data, where the selection of the model was based on that particular dataset (according to a formal likelihood ratio exam procedure). Thus, the model used for deriving the BMD in a unmarried generated dataset may not be the same as the one used for generating the data. In this way, model uncertainty is likewise taken into account. The results show that the operation of a blueprint is kickoff of all determined by the total number of animals used. Distributing them over more dose groups does non result in a poorer performance of the written report, despite the smaller number of animals per dose grouping. Dose placement is some other crucial factor; to minimize the hazard of inadequate dose placement the use of multiple dose studies is favorable. As a concomitant advantage, the utilize of multiple doses mitigates the disturbing effect of potential systematic errors in single dose groups. However, for endpoints with large remainder variation [coefficient of variation (CV)   ≥   xviii%] there is a substantial probability of not detecting the overall dose-response, and this probability increases in designs with increasing number of dose groups. In such situations, half dozen dose groups may be used equally a compromise. Designs with loftier-dose levels (i.east. associated with relatively high effects) are helpful in estimating doses with smaller effects (such as the BMD), and it appears bad do to omit higher dose groups to better the fit at lower doses. The typical 28-day study pattern of four dose groups with 5 animals (per sex) may not exist acceptable to assess endpoints with large residual variation (CV   ≥   18%), both for BMD and for NOAEL (Bokkers and Slob, 2005).

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Boron

S. Betharia , in Encyclopedia of Toxicology (Third Edition), 2014

Exposure Standards and Guidelines

Based on brute models, an NOAEL and a lowest observed adverse effect level (LOAEL) take been established at 55 and 76   mg   of   boron   kg−one  day−ane, respectively. Run a risk assessments of boron indicate no significant risk of toxicity to humans at currently estimated dietary or drinking water levels of exposure. The EPA has determined that exposure to boron in drinking h2o at concentrations of four   mg   50−1 for 1   day or 0.9   mg   l−1 for 10 days is not expected to cause no adverse effects in children. Also, the EPA has determined that a lifetime exposure to 1   mg   fifty−one boron is not expected to cause any adverse effects, and has set up the RfD for boron at 0.2   mg   kg−1  24-hour interval−1. The Us Occupational Safety and Wellness Assistants has express workers' exposure to an average of 15   mg chiliad−3 for boron oxide in air for an 8-h workday, xl-h workweek. The Bureau for Toxic Substances and Disease Registry has derived an astute-duration inhalational minimal risk level (MRL) equally 0.3   mg   boron   m−iii, an astute and intermediate elapsing oral MRL of 0.2   mg   boron   kg−one  day−1.

The inconsistency noted for prophylactic limits and estimated intakes reflects largely the variability of boron in man diets, with boron-poor regions providing less than 0.5   mg   boron   day–1 and boron-rich environments providing maximal intakes of 29   mg   boron   day–1 with even college intakes in rare instances. Evolving methods of collecting, processing, and analyzing samples and data are as well crusade for some variability, and even error, when determining boron in our human being surroundings.

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Dosing and Intervention

Richard Chin , Bruce Y. Lee , in Principles and Do of Clinical Trial Medicine, 2008

Determine the NOAEL for Each Animal Species

Use all available animal data to determine a NOAEL for each animal species tested. In this context, the NOAEL is the highest dose level that does not significantly increase agin effects (including biologically pregnant adverse effects that are not statistically significant) compared to the control grouping. Do non confuse the NOAEL with the NOEL, the highest dose at which no positive or negative furnishings (not only agin effects) are seen. Also, the NOAEL should exist lower than the LOAEL, the dose at which adverse effects are seen, and the MTD. Usually these agin furnishings are clinically evident (i.e., symptoms or a change in torso function), but sometimes nonclinical findings, such as appropriate surrogate markers (e.1000., ascent in serum liver enzyme levels), histopathological signs (e.g., microscopic lesions), and exaggerated pharmacodynamic effects, tin correspond agin furnishings. In some situations, data on bioavailability, metabolism, and distribution tin assist choose the NOAEL (e.thou., if maximum absorption occurs at a certain dose, apply that dose to calculate the human equivalent dose (HED). Even though higher doses may not produce whatever adverse furnishings, higher doses will not be beneficial because they will not result in higher plasma concentrations).

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Propanil

Marcia D. Howard , in Encyclopedia of Toxicology (Second Edition), 2005

Chronic Toxicity (or Exposure)

Animal

A 2 yr feeding study resulted in a no-observed-adverse-outcome level (NOAEL) of 600   ppm (15   mg   kg−1  day−1) in dogs. For rats, the NOAEL was 300   ppm (15   mg   kg−1  mean solar day−1) in a 3-generation reproductive study. Teratology studies in rats established an NOAEL of 20   mg   kg−1  day−1 (decreased pup size, delayed ossification at 100   mg   kg−i  day−one). Reproductive effects were observed only in exaggerated doses that were fatal to the mothers. Chronic effects from propanil exposure include centilobular enlargement of the liver, methemoglobinemia, decreased hemoglobin, and cyanosis although the dose levels producing these furnishings were many times greater than those expected from normal usage or exposure to the compound. Long-term exposure may result in kidney and liver impairment. There is no evidence of carcinogenicity in mice and rats.

Humans

Piffling is known regarding long-term effects of propanil. Methemoglobinemia would be expected.

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