9. GLOSSARY

Absorption-The taking up of liquids by solids, or of gases by solids or liquids.

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the

Toxicological Profiles.

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the

surfaces of solid bodies or liquids with which they are in contact.

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase)

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or

sediment.

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be

10%. The BMD is determined by modeling the dose response curve in the region of the dose response

relationship where biologically observable data are feasible.

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological

or epidemiological data to calculate a BMD.

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms

at a specific time or during a discrete time period of exposure divided by the concentration in the

surrounding water at the same time or during the same period.

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have

been classified as markers of exposure, markers of effect, and markers of susceptibility.

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces

significant increases in the incidence of cancer (or tumors) between the exposed population and its

appropriate control.

Carcinogen—A chemical capable of inducing cancer.

Case-Control Study—A type of epidemiological study which examines the relationship between a

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is

identified and compared to a similar group of people without outcome.

Case Report—Describes a single individual with a particular disease or exposure. These may suggest

some potential topics for scientific research but are not actual research studies.

CHROMIUM 416

9. GLOSSARY

Case Series—Describes the experience of a small number of individuals with the same disease or

exposure. These may suggest potential topics for scientific research but are not actual research studies.

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously.

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological

Profiles.

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed

group.

Cross-sectional Study—A type of epidemiological study of a group or groups which examines the

relationship between exposure and outcome to a chemical or to chemicals at one point in time.

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human

health assessment.

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result

from exposure to a chemical prior to conception (either parent), during prenatal development, or

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point

in the life span of the organism.

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a

toxicant and the incidence of the adverse effects.

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to

a chemical; the distinguishing feature between the two terms is the stage of development during which the

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water

levels for a chemical substance based on health effects information. A health advisory is not a legally

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials.

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of

disease or other health-related conditions within a defined human population during a specified period.

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of

affected cells, can be expressed as a mutagenic, clastogenic or carcinogenic event because of specific

alteration of the molecular structure of the genome.

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from

the body or environmental media.

CHROMIUM 417

9. GLOSSARY

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or

irreversible health effects.

Incidence—The ratio of individuals in a population who develop a specified condition to the total

number of individuals in that population who could have developed that condition in a specified time

period.

Intermediate Exposure—Exposure to a chemical for a duration of 15-364 days, as specified in the

Toxicological Profiles.

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from

exposure to environmental agents such as chemicals.

Immunological Effects—Functional changes in the immune response.

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube.

In Vivo—Occurring within the living organism.

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air which has been

reported to have caused death in humans or animals.

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for a

specific length of time is expected to cause death in 50% of a defined experimental animal population.

Lethal Dose(LO) (LDLO)—The lowest dose of a chemical introduced by a route other than inhalation that

has been reported to have caused death in humans or animals.

Lethal Dose(50) (LD50)—The dose of a chemical which has been calculated to cause death in 50% of a

defined experimental animal population.

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical

is expected to cause death in 50% of a defined experimental animal population.

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study,

or group of studies, that produces statistically or biologically significant increases in frequency or severity

of adverse effects between the exposed population and its appropriate control.

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the

lymph nodes, spleen, and thymus.

Malformations—Permanent structural changes that may adversely affect survival, development, or

function.

Minimal Risk Level (MRL) —An estimate of daily human exposure to a hazardous substance that is

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and

duration of exposure.

CHROMIUM 418

9. GLOSSARY

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a minimal risk

level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty

factors. The default value for a MF is 1.

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific

population.

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified

interval of time.

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s

DNA. Mutations can lead to birth defects, miscarriages, or cancer.

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of

death or pathological conditions.

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a

chemical.

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no

statistically or biologically significant increases in frequency or severity of adverse effects seen between

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not

considered to be adverse.

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical

in n-octanol and water, in dilute solution.

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances

and a disease or condition) which represents the best estimate of relative risk (risk as a ratio of the

incidence among subjects exposed to a particular risk factor divided by the incidence among subjects who

were not exposed to the risk factor). An odds ratio of greater than 1 is considered to indicate greater risk

of disease in the exposed group compared to the unexposed.

Organophosphate or Organophosphorus Compound—A phosphorus containing organic compound

and especially a pesticide that acts by inhibiting cholinesterase.

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA)

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek.

Pesticide—General classification of chemicals specifically developed and produced for use in the control

of agricultural and public health pests.

Pharmacokinetics—The science of quantitatively predicting the fate (disposition) of an exogenous

substance in an organism. Utilizing computational techniques, it provides the means of studying the

absorption, distribution, metabolism and excretion of chemicals by the body.

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based

CHROMIUM 419

9. GLOSSARY

and physiologically-based. A data-based model divides the animal system into a series of compartments

which, in general, do not represent real, identifiable anatomic regions of the body whereby the

physiologically-based model compartments represent real anatomic regions of the body.

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based doseresponse

model which quantitatively describes the relationship between target tissue dose and toxic end

points. These models advance the importance of physiologically based models in that they clearly

describe the biological effect (response) produced by the system following exposure to an exogenous

substance.

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments

representing organs or tissue groups with realistic weights and blood flows. These models require a

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar

ventilation rates and, possibly membrane permeabilities. The models also utilize biochemical information

such as air/blood partition coefficients, and metabolic parameters. PBPK models are also called

biologically based tissue dosimetry models.

Prevalence—The number of cases of a disease or condition in a population at one point in time.

Prospective Study—A type of cohort study in which the pertinent observations are made on events

occurring after the start of the study. A group is followed over time.

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the

incremental excess cancer risk per unit of exposure (usually µg/L for water, mg/kg/day for food, and

µg/m3 for air).

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health

(NIOSH) time-weighted average (TWA) concentrations for up to a 10-hour workday during a 40-hour

workweek.

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups)

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime.

The inhalation reference concentration is for continuous inhalation exposures and is appropriately

expressed in units of mg/m3 or ppm.

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level

(NOAEL-from animal and human studies) by a consistent application of uncertainty factors that reflect

various types of data used to estimate RfDs and an additional modifying factor, which is based on a

professional judgment of the entire database on the chemical. The RfDs are not applicable to

nonthreshold effects such as cancer.

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation

CHROMIUM 420

9. GLOSSARY

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a

24-hour period.

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior,

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of

this system.

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed

at some time in the past. Data are collected from routinely recorded events, up to the time the study is

undertaken. Retrospective studies are limited to casual factors that can be ascertained from existing

records and/or examining survivors of the cohort.

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical.

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or

inherited characteristic, that is associated with an increased occurrence of disease or other health-related

event or condition.

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed

group compared to the unexposed.

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 min

continually. No more than four excursions are allowed per day, and there must be at least 60 min

between exposure periods. The daily Threshold Limit Value - Time Weighted Average (TLV-TWA) may

not be exceeded.

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited

exposure to those assumed over a lifetime of exposure to a chemical.

Teratogen—A chemical that causes structural defects that affect the development of an organism.

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect.

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit

(STEL), or as a ceiling limit (CL).

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour

workday or 40-hour workweek.

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation,

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population.

CHROMIUM 421

9. GLOSSARY

Toxicokinetic—The study of the absorption, distribution and elimination of toxic compounds in the

living organism.

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to

account for (1) the variation in sensitivity among the members of the human population, (2) the

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-

adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data.

A default for each individual UF is 10; if complete certainty in data exists, a value of one can be used;

however a reduced UF of three may be used on a case-by-case basis, three being the approximate

logarithmic average of 10 and 1.

Xenobiotic—Any chemical that is foreign to the biological system.

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) (42 U.S.C.

9601 et seq.), as amended by the Superfund Amendments and Reauthorization Act (SARA) (Pub. L.

99–499), requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly

with the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances

most commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological

profiles for each substance included on the priority list of hazardous substances; and assure the initiation

of a research program to fill identified data needs associated with the substances.

The toxicological profiles include an examination, summary, and interpretation of available toxicological

information and epidemiologic evaluations of a hazardous substance. During the development of

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are

used by ATSDR health assessors to identify contaminants and potential health effects that may be of

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or

action levels.

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor

approach. They are below levels that might cause adverse health effects in the people most sensitive to

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently,

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level

above the MRL does not mean that adverse health effects will occur.

APPENDIX A

MRLs are intended only to serve as a screening tool to help public health professionals decide where to

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants,

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons

may be particularly sensitive. Thus, the resulting MRL may be as much as a hundredfold below levels

that have been shown to be nontoxic in laboratory animals.

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the

Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, with

participation from other federal agencies and comments from the public. They are subject to change as

new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in

the most recent toxicological profiles supersede previously published levels. For additional information

regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease

Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333.

APPENDIX A

Chemical name: Chromium

CAS number: 11115-74-5

Date: September, 2000

Profile status: Final

Route: [X] Inhalation [ ] Oral

Duration: [ ] Acute [X] Intermediate [] Chronic

Key to figure: 9

Species: Human

MRL: 0.000005 mg chromium(VI)/m3 as chromic acid (chromium trioxide mist) and other dissolved

hexavalent chromium aerosols and mists.

Reference: Lindberg E, Hedenstierna G. 1983. Chrome plating: Symptoms, findings in the upper

airways, and effects on lung function. Arch Environ Health 38:367-374.

Experimental design: (human study details or strain, number of animals per exposure/control group, sex,

dose administration details): Eighty-five male and 19 female chrome plating workers exposed to chromic

acid were assessed for nose, throat, and chest symptoms, were inspected for effects in nasal passages, and

were given pulmonary function tests. They were compared to a reference group of 119 auto mechanics

who were not exposed to chromium. The length of worker exposures to chromic acid ranged from 0.1 to

36 years. Chromium exposures were measured using personal air samplers and stationary equipment

positioned close to the baths containing chromic acid. The exposure categories were defined as high

average daily concentrations >0.002 mg chromium(VI)/m3], low (average daily concentrations <0.002 mg

chromium(VI)/m3), and mixed category (chromium(VI) was <0.002 mg chromium(VI)/m3 and there were

exposures to other acids and metallic salts). Correlations with nasal irritation and respiratory functions

were also determined for peak exposures. Statistical analyses were performed using the chi-square test

with Yate’s correction when comparing nasal findings, and the Student’s two tail t-test was used when

comparing lung function findings.

Effects noted in study and corresponding doses: Nasal irritation (p<0.05), mucosal atrophy (p<0.05), and

ulceration (p<0.01), and decreases in spirometric parameters (forced vital capacity, forced expired volume

in 1 second, and forced mid-expiratory flow) were observed in workers occupationally exposed to

$0.002 mg chromium(VI)/m3 as chromic acid with a median exposure period of 2.5 years. About 60% of

the exposed subjects were smokers, but no consistent association between exposure and cigarette smoking

was observed. Short-term peak exposures to chromic acid correlated better with nasal septum damage

than with 8-hour mean concentrations.

Dose endpoint used for MRL derivation: 0.002 mg chromium(VI)/m3 , adjusted to 0.0005 mg

chromium(VI)/m3 for continuous exposure, for respiratory effects.

[ ] NOAEL [X]LOAEL

APPENDIX A

Uncertainty factors used in MRL derivation:

[ ] 1 [ ] 3 [X] 10 (for use of a LOAEL)

[ ] 1 [ ] 3 [ ] 10 (for extrapolation from animals to humans)

[ ] 1 [ ] 3 [X] 10 (for human variability)

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No.

If so, explain: Not applicable.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: No.

Not applicable.

Was a conversion used from intermittent to continuous exposure? Yes, the LOAEL of 0.002 mg/m3 was

multiplied by 8 hr/24 hr and by 5 days/7 days to yield an adjusted LOAEL of 0.0005 mg/m3.

Other additional studies or pertinent information that lend support to this MRL:

The respiratory tract is the major target of inhalation exposure to chromium(III) and chromium(VI)

compounds in humans and animals. Respiratory effects due to inhalation exposure are probably due to

direct action of chromium at the site of contact. Intermediate- and chronic-duration exposure of workers

to chromium(VI) compounds has resulted in epistaxis, chronic rhinorrhea, nasal itching and soreness,

nasal mucosal atrophy, perforations and ulceration of the nasal septum, bronchitis, pneumonoconiosis,

decreased pulmonary function, and pneumonia (Bovet et al. 1977; Cohen et al. 1974; Davies et al. 1991;

Gomes 1972; Greater Tokyo Bureau of Hygiene 1989; Hanslian et al. 1967; Keskinen et al. 1980;

Kleinfeld and Rosso 1965; Lee and Goh 1988; Letterer 1939; Lieberman 1941; Lindberg and

Hedenstierm 1983; Lucas and Kramkowski 1975; Mancuso 1951; Meyers 1950; Novey et al. 1983;

Pastides et al. 1991; PHS 1953; Royle 1975b; Sassi 1956; Sluis-Cremer and du Toit 1968; Sorahan et al.

1987; Taylor 1966).

Agency Contact (Chemical Manager): Sharon Wilbur

APPENDIX A

Chemical name: Sodium dichromate

CAS number: 10588-01-9

Date: September, 2000

Profile status: Final

Route: [X] Inhalation [ ] Oral

Duration: [ ] Acute [X] Intermediate [ ] Chronic

Key to figure: 12

Species: Rat

MRL: 0.001 mg chromium (VI)/m3 as hexavalent chromium particulate compounds

Reference: Glaser U, Hochrainer D, Steinholf D. 1990. Investigation of irritating properties of inhaled

CrVI with possible influence on its carcinogenic action. Environ Hyg 2:235-245.

Experimental design: Eight-week old male Wistar rats (30 animals in each group) were exposed

22 hours/day, 7 days/week to 0, 0.05, 0.1, 0.2, or 0.4 mg chromium(VI)/m3 as sodium dichromate aerosol

particulates. Groups of 10 animals were sacrificed after 30 or 90 days of exposure or after 90 days of

exposure and a 30-day recovery period. The respective mass median mean diameters (MMAD) and

geometric standard deviation were 0.28 µm and 1.63 for the 0.5 and 0.1 mg/m3 concentrations and 0.39

µm and 1.72 for the 0.2 and 0.4 mg/m3 concentrations. Hematological, clinical chemistry, and urinalysis

tests were performed. Gross and histological examinations were limited to the upper airway epithelia, left

lung lobes, and the kidneys. In addition, lung lavage fluid was analyzed for total protein, albumin, lactate

dehydrogenase, and ß-glucuronidase activities.

Effects noted in study and corresponding doses: No deaths or abnormal clinical signs occurred at any of

the exposures. Body weight was significantly (p<0.001) decreased at 0.2 and 0.4 mg/m3 for 30 days, at

0.4 mg/m3 for 90 days (p<0.05), and at 0.2 (p<0.01) and 0.4 mg/m3 (p<0.05) in the recovery group. No

differences in urinary protein and no exposure-related histopathological lesions were noted. No

differences were seen in analysis of serum levels or activities of alanine aminotransferese, alkaline

phosphatase, glucose, urea, total bilirubin, total cholesterol, or phospholipids. There were no

hematological effects on red blood cells, but the white blood cell counts increased significantly in a

dose-related manner at 0.1–0.4 mg/m3 after 30 days and at 0.05 - 0.4 mg/m3 after 90 days. White blood

cells counts were not increased in 90 day exposure plus 30-day observation group.

Obstructive respiratory dyspnea occurred at 0.2 and 0.4 mg Cr(VI)/m3 after 30 and 90 days. Mean lung

weight was increased in all exposure groups and was statistically increased at 0.05 mg/m3 for 30 days, and

at 0.1 mg/m3 for 90 days and in the 90-day plus recovery period group. Histological examination

revealed slight hyperplasia in high incidence at 0.05 mg/m3 at 30 days. With longer exposure, the

incidence declined, indicating repair. Lung fibrosis occurred at 0.1 mg/m3 for 30 days, but was not seen

in rats exposed for 90 days. Accumulation of macrophages was observed in all exposed rats, regardless

of exposure concentration or duration. This histiocytosis probably accounts for the increased lung

weight. Histology of upper airways revealed focal inflammation. Results of bronchoalveolar lavage

(BAL) analysis provided further information of the irritation effect. Total protein in BAL fluid was

significantly increased in all exposed groups, but declined in the recovery period. Albumin in BAL fluid

APPENDIX A

increased in a dose-related manner at all concentrations in the 30-day group, but recovery started during

90-day exposure and continued during the 30-day observation period. The activities of lactate

dehydrogenase and ß-glucuronidase, measures of cytotoxicity, were elevated at 0.2 and 0.4 mg/m3 for

30 and 90 days, but returned to control values during the recovery period. The number of macrophages in

the BAL fluid had significantly increased after 30 and 90 days, but normalized during the recovery

period. The macrophages were undergoing cell division or were multinucleate and larger. This activation

of macrophages was not observed in the recovered rats. The study authors concluded that inflammation is

essential for the induction of most Chromium inhalation effects and may influence the carcinogenicity of

Chromium(VI) compounds.

Dose endpoint used for MRL derivation: 0.016 mg chromium(VI)/m3 for alterations in lactate

dehydrogenase in BAL fluid.

[ ] NOAEL [ ]LOAEL [ X ] benchmark concentration (BMC)

Uncertainty factors used in MRL derivation:

[ ] 1 [ ] 3 [ ] 10 (for use of a minimal LOAEL)

[ ] 1 [X] 3 [ ] 10 (for extrapolation from animals to humans)

[ ] 1 [ ] 3 [X] 10 (for human variability)

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No.

If so, explain: Not applicable.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose:

The Agency adopted the benchmark concentration analysis conducted by Malsch et al. (1994) for

deriving an intermediate-duration inhalation MRL. Using the 90-day exposure data, Malsch et al. (1994)

developed BMCs for lung weight, lactate dehydrogenase in the BAL fluid, protein in BAL fluid, and

albumin in BAL fluid. The concentration-effect data were adjusted for intermittent exposure

(22 hours/day) and the continuous data were fitted to a polynomial mean response regression model by

the maximum likelihood method. The BMCs (defined as the 95% lower confidence limit on the

concentration corresponding to a 10% relative change in the endpoint compared to the control) were

0.067, 0.016, 0.035, and 0.031 mg/m3, respectively. The lowest BMC, 0.016 mg/m3 for alterations in

lactate dehydrogenase levels in BAL fluid, was used to derive the MRL.

BMCADJ = BMC x RDDR

BMCADJ = 0.016 mg/m3 x 2.1576 = 0.034 mg/m3

where

RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure

concentration of an animal to the predicted inhalation particulate exposure concentration for a

human; based on a MMAD of 0.28 µm and a geometric standard deviation of 1.63, lung effects

(TH or thoracic region); RDDR calculated to be 2.1576 using Table H-1 (EPA, 1990—older

version of inhalation dosimetry methodology used to calculate RDDR because MMAD <0.5 µm,

so cannot use the EPA, 1994 program).

MRL = BMCADJ ÷ UF = 0.034 ÷ 30 = 0.001 mg Cr(VI)/m3

APPENDIX A

Was a conversion used from intermittent to continuous exposure? Yes.

Other additional studies or pertinent information that lend support to this MRL: The findings in this

study are supported by another 90-day study conducted by the same group (Glaser et al. 1985). In this

study, groups of 20 male Wistar rats were exposed to 0, 0.025, 0.05, 0.1, or 0.2 mg chromium(VI)/m3 as

sodium dichromate for 22 hours/day, 7 days/week for 90 days. No deaths occurred at any of the

exposures. All exposed animals showed normal histologic findings in lung, kidney, liver, stomach, and

gonads. Lung and spleen weights were increased significantly at doses above 0.025 mg

chromium(VI)/m3. Serum levels of triglycerides and phospholipid were increased in rats exposed to

0.2 mg chromium(VI)/m3. Serum contents of total immunoglobulins were significantly increased in the

0.05 and 0.1 mg chromium(VI)/m3 groups. At 0.025 and 0.2 mg chromium(VI)/m3, serum

immunoglobulin contents were no different than controls. The SRBC antibody response was increased in

all dosed groups over control values. Chromium treatment at 0.2 mg/m3 also enhanced the mitogenicstimulation

of splenic Concanavalin T-lymphocytes. At 0.025 mg chromium(VI)/m3, there were

significant increases in polynuclear macrophages, the number of macrophages in telophase, and increases

in lymphocytes in bronchoalveolar lavage samples. At 0.05 and 0.2 mg chromium(VI)/m3, there were

significant decreases in total numbers of macrophages. The percentages of polynuclear macrophages,

lymphocytes, and granulocytes were increased at chromium exposures of 0.05 mg chromium(VI)/m3, but

at 0.2 mg chromium(VI)/m3 the percentage of granulocytes cells was lower than control values. At

0.025 and 0.05 mg chromium(VI)/m3 exposures, phagocytosis of latex particles by alveolar macrophages

was increased over controls. However, at 0.2 mg chromium(VI)/m3, the phagocytic activity was less than

controls and there was a decrease in lung clearance of iron oxide particulates.

Agency Contact (Chemical Manager): Sharon Wilbur

This chapter of the profile is a health effects summary written in non-technical language. Its intended

audience is the general public especially people living in the vicinity of a hazardous waste site or

chemical release. If the Public Health Statement were removed from the rest of the document, it would

still communicate to the lay public essential information about the chemical.

The major headings in the Public Health Statement are useful to find specific topics of concern. The

topics are written in a question and answer format. The answer to each question includes a sentence that

will direct the reader to chapters in the profile that will provide more information on the given topic.

Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects and illustrate

graphically levels of exposure associated with those effects. These levels cover health effects observed at

increasing dose concentrations and durations, differences in response by species, minimal risk levels

(MRLs) to humans for noncancer end points, and EPA's estimated range associated with an upper- bound

individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a

quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and

figures should always be used in conjunction with the text. All entries in these tables and figures

represent studies that provide reliable, quantitative estimates of No-Observed-Adverse- Effect Levels

(NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs).

The legends presented below demonstrate the application of these tables and figures. Representative

examples of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends

correspond to the numbers in the example table and figure.

(1) Route of Exposure One of the first considerations when reviewing the toxicity of a substance using

these tables and figures should be the relevant and appropriate route of exposure. When sufficient

data exists, three LSE tables and two LSE figures are presented in the document. The three LSE

tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE

Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1)

and oral (LSE Figure 2-2) routes. Not all substances will have data on each route of exposure and

will not therefore have all five of the tables and figures.

APPENDIX B

(2) Exposure Period Three exposure periods - acute (less than 15 days), intermediate (15–364 days),

and chronic (365 days or more) are presented within each relevant route of exposure. In this

example, an inhalation study of intermediate exposure duration is reported. For quick reference to

health effects occurring from a known length of exposure, locate the applicable exposure period

within the LSE table and figure.

(3) Health Effect The major categories of health effects included in LSE tables and figures are death,

systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and

LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are

further defined in the "System" column of the LSE table (see key number 18).

(4) Key to Figure Each key number in the LSE table links study information to one or more data points

using the same key number in the corresponding LSE figure. In this example, the study represented

by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (also see the 2

"18r" data points in Figure 2-1).

(5) Species The test species, whether animal or human, are identified in this column. Section 2.5,

"Relevance to Public Health," covers the relevance of animal data to human toxicity and Section

2.3, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although

NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses

to derive an MRL.

(6) Exposure Frequency/Duration The duration of the study and the weekly and daily exposure

regimen are provided in this column. This permits comparison of NOAELs and LOAELs from

different studies. In this case (key number 18), rats were exposed to 1,1,2,2-tetrachloroethane via

inhalation for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review of the

dosing regimen refer to the appropriate sections of the text or the original reference paper, i.e.,

Nitschke et al. 1981.

(7) System This column further defines the systemic effects. These systems include: respiratory,

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular.

"Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems.

In the example of key number 18, 1 systemic effect (respiratory) was investigated.

(8) NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no

harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm

for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of

0.005 ppm (see footnote "b").

(9) LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the study

that caused a harmful health effect. LOAELs have been classified into "Less Serious" and

"Serious" effects. These distinctions help readers identify the levels of exposure at which adverse

health effects first appear and the gradation of effects with increasing dose. A brief description of

the specific endpoint used to quantify the adverse effect accompanies the LOAEL. The respiratory

effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not

derived from Serious LOAELs.

(10) Reference The complete reference citation is given in chapter 8 of the profile.

(11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of

carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious

APPENDIX B

effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report

doses not causing measurable cancer increases.

(12) Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in

the footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to derive an

MRL of 0.005 ppm.

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the

reader quickly compare health effects according to exposure concentrations for particular exposure

periods.

(13) Exposure Period The same exposure periods appear as in the LSE table. In this example, health

effects observed within the intermediate and chronic exposure periods are illustrated.

(14) Health Effect These are the categories of health effects for which reliable quantitative data exists.

The same health effects appear in the LSE table.

(15) Levels of Exposure concentrations or doses for each health effect in the LSE tables are graphically

displayed in the LSE figures. Exposure concentration or dose is measured on the log scale "y" axis.

Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in mg/kg/day.

(16) NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation

exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates

to a NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table.

The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see

entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table).

(17) CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond

symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to

the entry in the LSE table.

(18) Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the

upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the

cancer dose-response curve at low dose levels (q1*).

(19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure.

APPENDIX B

1 6 TABLE 2-1. Levels of Significant Exposure to [Chemical x] – Inhalation

Key to

figurea Species

Exposure

frequency/

duration System

NOAEL

(ppm)

LOAEL (effect)

Reference Less serious (ppm) Serious (ppm)

2 6 INTERMEDIATE EXPOSURE

5 6 7 8 9 10

3 6 Systemic 9 9 9 9 9 9

4 6 18 Rat 13 wk

5d/wk

6hr/d

Resp 3b 10 (hyperplasia) Nitschke et al.

1981

CHRONIC EXPOSURE

11

Cancer 9

38 Rat 18 mo

5d/wk

7hr/d

20 (CEL, multiple

organs)

Wong et al. 1982

39 Rat 89–104 wk

5d/wk

6hr/d

10 (CEL, lung tumors,

nasal tumors)

NTP 1982

40 Mouse 79–103 wk

5d/wk

6hr/d

10 (CEL, lung tumors,

hemangiosarcomas)

NTP 1982

a The number corresponds to entries in Figure 2-1.

12 6 b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10-3 ppm; dose adjusted for intermittent exposure and divided by

an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability).

APPENDIX B

(=14 days)

10-4

10-5

10-6

10-7

Risk Levels Key

APPENDIX B

The Relevance to Public Health section provides a health effects summary based on evaluations of

existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present

interpretive, weight-of-evidence discussions for human health end points by addressing the following

questions.

1. What effects are known to occur in humans?

2. What effects observed in animals are likely to be of concern to humans?

3. What exposure conditions are likely to be of concern to humans, especially around hazardous

waste sites?

The section covers end points in the same order they appear within the Discussion of Health Effects by

Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are

presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro

data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered

in this section. If data are located in the scientific literature, a table of genotoxicity information is

included.

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer

potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if

derived) and the end points from which they were derived are indicated and discussed.

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public

health are identified in the Data Needs section.

Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for

inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These

MRLs are not meant to support regulatory action; but to acquaint health professionals with exposure

levels at which adverse health effects are not expected to occur in humans. They should help physicians

and public health officials determine the safety of a community living near a chemical emission, given the

concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on

toxicological studies in animals and on reports of human occupational exposure.

MRL users should be familiar with the toxicologic information on which the number is based. Chapter

2.5, "Relevance to Public Health," contains basic information known about the substance. Other sections

such as 2.7, "Interactions with Other Substances,” and 2.8, "Populations that are Unusually Susceptible"

provide important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a

modified version of the risk assessment methodology the Environmental Protection Agency (EPA)

provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (RfDs).

APPENDIX B

To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement,

represents the most sensitive human health effect for a given exposure route and duration. ATSDR

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available

for all potential systemic, neurological, and developmental effects. If this information and reliable

quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive

species (when information from multiple species is available) with the highest NOAEL that does not

exceed any adverse effect levels. When a NOAEL is not available, a lowest-observed-adverse-effect

level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed.

Additional uncertainty factors of 10 must be used both for human variability to protect sensitive

subpopulations (people who are most susceptible to the health effects caused by the substance) and for

interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual

uncertainty factors are multiplied together. The product is then divided into the inhalation concentration

or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL

are provided in the footnotes of the LSE Tables.

ACGIH American Conference of Governmental Industrial Hygienists

ADME Absorption, Distribution, Metabolism, and Excretion

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry

BCF bioconcentration factor

BSC Board of Scientific Counselors

C Centigrade

CDC Centers for Disease Control

CEL Cancer Effect Level

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFR Code of Federal Regulations

CLP Contract Laboratory Program

cm centimeter

CNS central nervous system

d day

DHEW Department of Health, Education, and Welfare

DHHS Department of Health and Human Services

DOL Department of Labor

ECG electrocardiogram

EEG electroencephalogram

EPA Environmental Protection Agency

EKg see ECG

F Fahrenheit

F1 first filial generation

FAO Food and Agricultural Organization of the United Nations

FEMA Federal Emergency Management Agency

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

fpm feet per minute

ft foot

FR Federal Register

g gram

GC gas chromatography

gen generation

HPLC high-performance liquid chromatography

hr hour

IDLH Immediately Dangerous to Life and Health

IARC International Agency for Research on Cancer

ILO International Labor Organization

in inch

Kd adsorption ratio

kg kilogram

kkg metric ton

Koc organic carbon partition coefficient

Kow octanol-water partition coefficient

L liter

LC liquid chromatography

CHROMIUM C-2

APPENDIX C

LCLo lethal concentration, low

LC50 lethal concentration, 50% kill

LDLo lethal dose, low

LD50 lethal dose, 50% kill

LOAEL lowest-observed-adverse-effect level

LSE Levels of Significant Exposure

m meter

MCV mean corpuscular volume

mg milligram

min minute

mL milliliter

mm millimeter

mmHg millimeters of mercury

mmol millimole

mo month

mppcf millions of particles per cubic foot

MRL Minimal Risk Level

MS mass spectrometry

NIEHS National Institute of Environmental Health Sciences

NIOSH National Institute for Occupational Safety and Health

NIOSHTIC NIOSH's Computerized Information Retrieval System

ng nanogram

nm nanometer

NHANES National Health and Nutrition Examination Survey

nmol nanomole

NOAEL no-observed-adverse-effect level

NOES National Occupational Exposure Survey

NOHS National Occupational Hazard Survey

NPL National Priorities List

NRC National Research Council

NTIS National Technical Information Service

NTP National Toxicology Program

OSHA Occupational Safety and Health Administration

PEL permissible exposure limit

pg picogram

pmol picomole

PHS Public Health Service

PMR proportionate mortality ratio

ppb parts per billion

ppm parts per million

ppt parts per trillion

REL recommended exposure limit

RfD Reference Dose

RTECS Registry of Toxic Effects of Chemical Substances

sec second

SCE sister chromatid exchange

SIC Standard Industrial Classification

SMR standard mortality ratio

STEL short term exposure limit

STORET STORAGE and RETRIEVAL

TLV threshold limit value

TSCA Toxic Substances Control Act

CHROMIUM C-3

APPENDIX C

TRI Toxics Release Inventory

TWA time-weighted average

U.S. United States

UF uncertainty factor

yr year

WHO World Health Organization

wk week

> greater than

> greater than or equal to

= equal to

< less than

< less than or equal to

% percent

a alpha

ß beta

d delta

? gamma

µm micrometer

µg microgram

see also:

Sec 4 - IMPORT/EXPORT Toxicological Profile for Chromium - Agenct for Toxic Substances
Agenct for Toxic Substances: Toxicological Profile for Chromium

Sec 5 - HUMAN EXPOSURE Toxicological Profile for Chromium - Agenct for Toxic Substances
Agenct for Toxic Substances: Toxicological Profile for Chromium

Complete Toxicological Profile for Chromium Toxicological Profile for Chromium - Agenct for Toxic Substances
Agenct for Toxic Substances: Toxicological Profile for Chromium