The terms toxicology, toxicity, or toxic substance toxicant are used daily in the scientific and general literature.. Lippmann 1992, Environmental toxicants: human exposures and their
Trang 1The terms toxicology, toxicity, or toxic substance ( toxicant )
are used daily in the scientific and general literature Review
of almost any daily newspaper will reveal one or more
arti-cles on the toxic effects of a substance, most of which when
released into the environment are called pollutants Today
there are scientific journals devoted to the subject of toxicity,
illustrating the importance of this topic However, many do
not understand the term toxicology or have an understanding
of its concepts So what is a good definition of toxicity? It
can be best defined as the science of poisons Of course, this
brings us to the question of what a poison is: any substance
that can result in a detrimentaleffect when the concentration
is increased An increased response as compared to increasing
concentration has been called a “dose-response curve,” which
will be discussed later
When using the definition of toxicity provided above,
most will consider poisoning of animals and humans;
how-ever, this definition can be extended to all life forms,
includ-ing microbes (Thomulka et al., 1996) and plants (Haarmann
and Lange, 2000) In the broadest term, toxic insult can be
evaluated from an ecological viewpoint and can encompass
effects to an ecosystem This is what is commonly
consid-ered when looking at poisoning in an industrial environment
However, in today’s changing environment, the viewpoint
from an industrial perspective is changing to include the entire
environment The scope of toxicology is ever-increasing,
and from the point of view of an engineer, especially an
envi-ronmental engineer, should not be limited Depending on the
focus, toxicity can also be viewed from global impact (e.g.,
mercury release from burning fossil fuels) to that which affects
single-celled organisms in a local pond
Public awareness has raised the term toxicity to an
every-day usage, although most do not understand how to properly
apply this term Most consider that when something is listed
as toxic it means an effect from an exposure has occurred
Certainly in the most general sense this is true Forgotten
for the term toxicity is that every substance is toxic, at least
in the right dose So what can be added to the concept of a
poison is that the dose makes the poison
For engineers, often the terms hazardous substance or
waste are used as substitutes for toxicity This in the strict
definition is not correct, in that a hazardous waste may not
act as a poison, but rather result in a physical effect (e.g., a
burn) However, even a substance capable of causing a burn
will do so in proportion to the concentration applied Thus,
even for these types of substances, there is a dose-response
effect If any effect from a substance is considered a toxic
response, then hazardous waste is another name for toxicity
In most cases a hazardous waste is a mixture of substances andⲐor chemicals at a site, and its release was uncontrolled or
unregulated Regardless, this mixture will have its own dose-response, while the individual chemicals or substances will exhibit separate responses (a differing dose-response curve)
What is of importance to many engineers when examining toxicity is the use of standard references Table 1 lists number
of textbooks and governmental sources that contain various numerical values for toxicity and basic information on chemi-cals These sources are a very good staring point to obtain basic information about a chemical, its regulatory limits, and general information on the hazards associated with the substance
AREAS OF TOXICOLOGY
Toxicology can be divided into a variety of subareas These areas can be categorized by organ systems, chemicals (substances),
or discipline Examples of categorization are shown in Table 2, along with a brief description For the most part, engineers will work in the general areas of environmental and occupational toxicology, although some will venture into others as well In special cases, engineers will venture into areas such as forensic toxicology What needs to be kept in mind is that toxicology is
an area that borrows from other basic fields of science, such as chemistry, physics, biology, and mathematics
ENDPOINTS OF TOXICITY
Historically, toxicology was associated with the response of animals when exposed to an agent or agents Mostly this has been performed using small rodents such as mice and rats
However, for engineers, animal toxicity data are only one part, especially for work that relates to the environmental areas For example, evaluation of a hazardous-waste site can involve the toxic effects to plants, invertebrates, microbes, and aquatic organisms Commonly, toxicity of a substance or toxicant
is often referred to a single organism In the environmental area, as well as in others, there may be many different types of organisms affected, along with different effects among these organisms Use of a single value will not likely represent toxicity to entire groups or a system Thus, representation of toxicity as a single value may be misleading Toxicity end-points for a chemical can vary by logarithmic orders, even for
Trang 2TABLE 1 Some common references on environmental and occupational toxicology
Klaassen CD (1996), Casarett and Doulls Toxicology:
the basic science of poisons
An excellent reference on toxicology, although generally written at the graduate level.
which provide the upper exposure limit for many chemicals.
Hathaway et al (1991), Proctor and Hughes’ chemical hazards of
the workplace
Provides information on many chemicals—including regulatory exposure limits and basic information on the chemical.
OSHA (29 CFR 1910 1000) Permissible exposure limits (PELs), which are the maximum exposure limit
set by the U.S government.
NIOSH Criteria Documents Information on a specific chemical as provided by NIOSH However, these
reports are not updates and some that are older will not have the most up-to-date information.
Niesink et al (1995), Toxicology: principles and applications General toxicology reference that focuses on the occupational environment.
Lippmann (1992), Environmental toxicants: human exposures and their
health effects
Provides information through chapters on specific topics that relate to both environmental and occupational toxicology.
Rand and Petrocelli (1985), Fundamentals of aquatic
toxicology: methods and applications
A good basic textbook on aquatic toxicology.
NIOSH (1994), NIOSH pocket guide to hazardous chemicals Provides exposure values, physical properties, and keywords on health
hazards for many chemicals of industrial interest.
ACGIH ® —American Conference of Governmental Industrial Hygienists
OSHA—U.S Occupational Safety and Health Administration
NIOSH—National Institute for Occupational Safety and Health (an example of these documents is NIOSH, Criteria for recommended standard
occupational exposure to hydrogen fluoride, Department of Health and Human Services (DHHS) (NIOSH) Pub Nos 76–141)
the same organism This is illustrated by the chemical copper
for Strongylocentrotus purpuratus using the endpoint EC 50 ,
which is the median effective concentration (where 50% of
the organisms are affected at a given period of time) ED 50 is
the median exposure dose,which is the concentration in air
or water The other commonly used endpoint of measure for
industrial (occupational) toxicology is the median lethal dose
(LD 50 ; again, this is a value where 50% of the organisms die at
the given concentration, assuming that the mean and median
values are equal, as in a normal curve, although used in more
studies to refer to the median concentration) Obviously the
LD 50 is not useful in setting occupational-exposure limits, but
provides a relative comparison for different chemicals Similar
in nature to the LD50 is the EC 50 Here the concentration has
to be in some unit of air or liquid (water) for the endpoint
to be measured The variability for a chemical as related to effective endpoints (dose) can be illustrated using copper in aquatic organisms (Table 3) The LD 50 of copper for the vari-ous organisms listed have a large variation (log order) This variation is commonly observed when evaluating a chemi-cal among different organisms and even the same organism between laboratories
A toxic response can be reported as any endpoint mea-surement that is reproducible This can include death, as rep-resented by an LD 50 or another, such as a behavior endpoint measurement, which could be an EC 50 When evaluating
TABLE 2 Some areas of toxicology
be considered pollution This can be further divided into air, soil, and water systems There can also be a measurement on a species as well.
other organisms, such as livestock, that is in relation
to a crime.
working environment and industry.
the risk associated with the purposes or in some cases prevention of that chemical’s use This is often associated with some regulation or law, like the U.S Clean Air Act (CAA).
this action causes a toxic effect on the organism.
TABLE 3 Aquatic toxicology values of various organisms for copper
Mesocyclops peheiensis 75 g/l Wong and Pak, 2004
Tilapia zillii 6.1 mg/l Zyadah and
Abdel-Baky, 2000
Mysis sp (from Nile River) 2.89 mg/1 Zyadah and
Abdel-Baky, 2000
Mugil cephalus 5.3 mg/1 Zyadah and
Abdel-Baky, 2000
Photobacterium phosphoreum ⬎100 mg/1 Thomulka
et al., 1993
Strongylocentrotus purpuratus 15.3 g/1 ⫹ Phillips
et al., 2003
Penaes merguiensis 0.38 mg/1 Ahsanullah and Ying,
1995
⫹ An EC 50
Trang 3data, the endpoint must be identified, especially when
look-ing at nonlethal measurements such as EC 50 ’s
There are three general routes of exposure: inhalation,
dermal (skin), and ingestion (oral) A fourth route, which is
more related to medical situations, is injection Depending on
the chemical and the activity employed, one or more of these
will have a great deal of importance in the toxic outcome
Occupationally, the most important route is inhalation, since
it generally results in the most severe health consequences
Dermal effects are the most numerous, but in most cases are
of minor importance Most dermal effects are related to
irri-tation of the skin and related allergic reactions As a general
rule in occupational toxicology, skin problems are the most
common, although effects such as cancer of various organs
can also be of concern (Lange, 2003) Using cement as an
example, epidemiological studies have reported this agent to
cause cancer in a variety of organs The organs or systems
of carcinogenic concern include the skin, bladder, stomach,
and lungs (Smailyte et al., 2004), although the most common
problem reported in occupations using this building material
is dermatological (skin) (Winder and Carmondy, 2002; Lange,
2003), which is a noncarcinogenic occupational hazard This
illustrates that a chemical can have multiple toxic endpoints
for different organs
Most toxicologists divide the exposure to humans and
organisms into four categories: acute, subacute, subchronic,
and chronic Acute is commonly defined as a single or repeated
exposure that occurs over a 24-hour period that results in a
measurable effect Although this definition is not perfect, it
tells us that acute cases are generally of short duration and
high concentration Subacute, on the other hand, is exposure
that occurs over about a 1-month time period and in this case
is generally lower in concentration, and the effect requires a
longer period of time to occur in comparison to a true acute
exposure It is not uncommon to report acute effects as case
studies In the case report by Dote et al (2003), an industrial
worker accidentally exposed (sprayed) himself with the agent
hydrogen fluoride (HF), or hydrofluoric acid HF is a highly
corrosive agent that can result in serous chemical burns, and
in this case the burns occurred on the face of the industrial
worker As a result of this exposure, the worker died within a
half hour as a result of acute respiratory failure In the case of
HF, this substance would be considered a hazard to both the
respiratory and dermal systems, in this case inhalation being
the main route of exposure that resulted in death To put HF
exposure in perspective, Hathaway et al (1991) reported that
the LD 50 for a 5-minute exposure is between 500 and 800
parts per million (ppm)
Chronic toxicology is defined as an effect resulting from
an exposure that occurs over a long period of time, like years
Certainly the time period of measurement also depends on the
length of an organism’s life history as well Subchronic, as
compared to chronic, is of shorter duration with a higher
con-centration and can be considered to occur within a time period
of 1 to 3 months for people Although these terms are
dis-cussed for an occupational setting, the terms are also applied to
environmental toxicology Historically, acute exposure was a
key factor in exposure prevention As industrial exposures are
becoming better controlled, there has been a change in focus to chronic conditions, at least in the developed countries
Since inhalation is the most important route of exposure
in the occupational (industrial) environment, most reported limits of acceptable exposure are for this route However, in other systems, such as aquatic or terrestrial, dermal contact
or ingestion may be the most important routes of exposure
OCCUPATIONAL EXPOSURE LIMIT VALUES
For occupational exposure, established upper limits have been published by governmental and private agencies or groups
These values are: permissible exposure limit (PEL), thresh-old limit value (TLV), and recommended exposure limit (REL) PELs are established by the U.S Occupational Safety and Health Administration (OSHA) and are the legal stan-dard for the maximum exposure level OSHA PELs are pub-lished in the Code of Federal Regulations (CFR) at 29 CFR 1910.1000 It should be noted that these exposure concentra-tions are mostly for inhalation, as previously mentioned, and the levels represented are somewhat out of date, since they have to go through a regulatory process for updating TLVs are established by the American Conference of Governmental Industrial Hygienists (ACGIH), which is considered a consen-sus organization Many consider these values to be the most up-to-date, although they are, like most decision-making pro-cesses, subject to industry pressure and other political factors when being established Generally, TLVs are lower in concen-tration than PELs, although there are exceptions to this state-ment It can be considered that the PELs, as they change, are also subject to industry and political considerations as well
Both the PELs and TLVs are established for an 8-hour time-weighted average (TWA) This average is an arithmetic mean
of all the exposures collected in that workday The formula for making a TWA is shown below
TWA ⫽ ( C 1 ⫻ T 1 ) ⫹ ( C 2 ⫻ T 2 ) ⫹ ⫹ ( C n ⫻ T n )Ⲑ
( T 1 ) ⫹ ( T 2 ) ⫹ ⫹ ( T n )
C —concentration
T —time
The maximum and ideal time of sample (exposure) col-lection is 8 hours, although this is not usually feasible Most consider that to obtain a TWA the sample should be collected for at least 6.5 hours of the 8-hour work shift The remaining 1.5 hours would be included as a 0 exposure level The REL
is a 10-hour TWA exposure limit and is set by the National Institute of Occupational Safety and Health (NIOSH) as a value to be considered by OSHA in the rule-making process
For all the values (PEL, TLV, and REL), they are established for a 40-hour workweek
When evaluating exposure limits, exceedance can be considered for a single measurement or summation of mea-surements (Letters to the Editor, 1998) There has been considerable discussion of the correct evaluation for expo-sure For those chemicals that are considered to be chronic
in nature, disease appears to follow the arithmetic mean of
Trang 4exposure, suggesting that summation exposure values best
represent potential health effects (Lange, 2002)
A short-term exposure limit (STEL) has also been
estab-lished for many chemicals STELs are for 15-minute periods
with at least 2 hours of exposure below the PEL, as an
exam-ple, with no more than four exposure periods (STELs)
occur-ring per day When applying STELs, the PEL should not be
exceeded when these values are included in the TWA If there
is an exceedance of the PEL, appropriate personal protective
equipment is then required
Exposure limit values (TLV-TWA) are established using
three general criteria First, in order of importance, are
epi-demiological data Occupational and in some cases
environ-mental epidemiology studies provide the most important
information on the hazards from a chemical Since there
are different types of epidemiological studies, those of the
greatest strength, in order, are: cohort, case-control,
cross-sectional, and ecological Next is animal experimentation in
identifying hazards, and last are case studies or reports The
ACGIH publishes documentation summarizing the basis for
establishing and setting TLVs and is often useful as a general
reference Another good reference that provides summary
information on chemicals is Hathaway et al (1991)
Exposure levels are given in units of mgⲐm 3 , ppm, and
fibers per cubic centimeter (fⲐcc) In most cases these values
are for inhalation, but there are some listed for skin (e.g.,
decaborane)
Another value that is of importance to toxicologists in the
industrial environment is IDLH (immediately dangerous to life
and health) The problem with IDLH is that it has two
differ-ent definitions (NIOSHⲐOSHAⲐUSCGⲐEPA, 1985) The Mine
Safety and Health Administration (MSHA) (30 CFR 11.3[t])
defines IDLH as the concentration that will cause immediate
death of permanent injury However, NIOSH, in the Pocket Guide (1994; see Table 1), defines this as the maximum
con-centration where one can escape within 30 minutes without irreversible health effects So care must be taken when using IDLH values, as each source has completely different criteria
DOSE-RESPONSE
In toxicity there exists an increased response to a chemical with the chemical’s increasing concentration This is known
as the “dose-response effect” and is fundamental to toxicol-ogy In general, it can be said that every chemical has a dose-response effect The dose-response is any repeatable indicator or measurement that is used to evaluate the response of an organ-ism to the chemical At some point the concentration becomes high enough that the response is 100% Figure 1 shows time
of exposure to various concentrations of the chemical sodium bisulfate (Haarmann and Lange, 2000) As the concentration
of each chemical varies there is a reduction in root length after
a given period of time In many cases the curve would appear reversed, where there would be no inhibition at the lower con-centrations and inhibition at the higher levels However, here, for the root length, which was for radish-seed elongation, the highest length is at the lower concentration of chemical
The shape of the dose-response curve can provide informa-tion on the effect of a chemical, and data extracted from this relationship is often used in risk-assessment analysis LD 50 and related values are extracted from dose-response curves
Different formulas can be used to obtain this information as well (Thomulka et al., 1996)
Sodium Bisulfate (ppm) 0
20 40 60 80 100 120 140
FIGURE 1 Dose-response curve for sodium bisulfate in Lake Erie water (from Haarmann and Lange, 2000; with permission from Parlar Scientific Publications).
Trang 5Dose-response curves are often used to provide
informa-tion on a chemical as well as comparison to other chemicals
Potency is one factor that can be derived from the
dose-response This term refers to the concentrations that result in
an increasing response to the chemical Two chemicals can
have the same slope on a dose-response curve, but have
dif-ferent potencies Thus, various information can be extracted
from dose-response curves
EXPOSURE
Exposure can be considered to be at the heart of toxicology
Just because you are exposed does not mean that there will
be an effect or even that the chemical will be taken up by the
organism There are a number of factors that influence the
cause and effect, including absorption, distribution,
excre-tion, and biotransformation To understand exposure, a brief
discussion of each will be presented
A toxicant is often called a xenobiotic, which means a
foreign substance, and these terms are often used
interchange-ably in texts In some cases, a xenobiotic may not be foreign
to the organism (e.g., selenium), but exist in a higher or lower
concentration that results in a disease state Of importance
to environmental and occupational toxicology is that a lower
concentration may also result in disease or an undesired event,
which for the purposes of this chapter will be considered a
toxic action In some unusual cases increased occupational
exposure has been reported to result in beneficial effects
This has been illustrated by the exposure of organic dust that
appears to reduce lung cancer (Lange, 2000; Lange et al.,
2003) However, it needs to be noted that exposure to organic
dust (like cotton dust, in the textile industry) also results in
severe respiratory diseases (e.g., bysinosis), which outweigh
any benefits of reduced lung cancer, as in this case
Absorption
Absorption is the process where a xenobiotic crosses a
mem-brane or barrier (skin) and enters the organism, most
com-monly into the blood As previously mentioned, the major
routes of absorption are ingestion (the gastrointestinal [GI]
system), inhalation (lungs), and dermal (skin) Oral intake
is not a common route of occupational exposure, but one of
major importance environmentally Transport across barriers
occur as passive transport, active transport, facilitated
dif-fusion, or specialized transport Transport can occur in the
uptake and excretion of chemicals Passive transport, which
is simple diffusion, follows Frick’s Law and does not require
energy Here a concentration gradient exists, and molecules
move from the higher to the lower concentration As a rule,
for biological systems, the more nonionized the form of a
molecule, the better it is transported across lipid membranes
The membranes of cells are composed of a lipid bilayer, thus
favoring nonionized compounds Active transport involves
the movement of a chemical against a gradient and requires
the use of energy This requires a transporter molecule to
facilitate the movement and would be subject to saturation
of the system Facilitated transport is similar to active trans-port, except it does not work against a gradient and does not require energy There are other specialized forms of transport, such as phagocytosis by macrophages These various transport mechanisms are also used to bring essential substances and xenobiotics into the organisms
Absorption in the GI tract can occur anywhere from the mouth to the rectum, although there are some generalizations that can be made If the chemical is an organic acid or base,
it will most likely be absorbed in locations where it exists
in its most lipid-soluble form The Henderson-Hasselbalch equation can be used to determine at what pH a chemical exists as lipid-soluble (nonionized) as compared to ionized
As a general rule, ionized forms of a chemical are not easily absorbed across biological membranes
For the lungs, gases, vapors, and particles can be absorbed In the lungs, ionization of a chemical is not as important as it is for the GI tract This is due to the rapid absorption of chemicals and the thinness of the separation
of alveolar cells (air in the lungs and blood system) with the body fluids (blood) Ionized molecules are also generally nonvolatile and are therefore usually not in high concentra-tion in the air Particles are separated as they travel the pul-monary system The larger ones (say, greater than 10 m in size) are removed early in the pulmonary system, like in the nasal area, whereas the smaller ones (say, 1 m) enter the alveolar region As a general rule, it can be said that particles around 5 to 10 m are deposited in the nasopharyngeal area, those 2 to 5 m in the tracheobronchial area, and those less than 1 to 2 m in the alveolar region The alveolar region
is where air is exchanged with the blood system, oxygen is taken up, and waste gases (carbon dioxide) are returned to the atmosphere Particles that are deposited into the alveolar region have been termed “respirable dust” (Reist, 1993)
Distribution of particles described is not exact, but provides
a generalization of particle distribution for lungs Some chemicals, like those that are highly water-soluble (e.g., formaldehyde), can be scrubbed out at various locations of the respiratory tract Here, formaldehyde is removed by the nose, and in general this is a site of its toxic action, irritation, and nasal cancer (Hansen and Olsen, 1995)
Skin is generally not highly penetrable and is a good overall protective barrier This protection is a result of the multiple layers of tissue associated with the skin However, the primary layer of protection is the stratum corneum This
is the top layer of cells on the skin; it is dead and can vary in thickness On the hands and feet this cell layer can be 400 to
600 m thick, while on the legs it can be 8 to 15 m Some chemicals can disrupt the skin’s protection and allow chemi-cals to pass more easily An example of this is dimethyl sulf-oxide (DMSO), which can de-fat the skin and allow better penetration of chemicals
Distribution
After a chemical enters the organism, it is usually distributed rapidly This distribution is commonly achieved by the blood system Many chemicals have locations in the organism where
Trang 6they concentrate (e.g., lead in bone) It is often important to
know where a chemical is concentrated or its organ of
toxic-ity Some generalities, although not complete, can be made
for different classes of compounds (Table 4) However, when
evaluating toxicity it is necessary to obtain specific
informa-tion on the compound because there are many excepinforma-tions to
general rules of site of toxic action It is not uncommon that
one chemical will have multiple organs or locations of
toxic-ity A good example of this is the metal arsenic Arsenic can be
both an environmental and occupational poison Ingestion of
arsenic in drinking water, at elevated concentrations, has been
shown to result in skin cancer (which has been referred to as
Blackfoot disease) as well as other forms of cancer (e.g., lung;
Bhamra and Costa, 1992) and noncancer diseases (e.g.,
der-matological; Lange, 2004a) Environmental problems
associ-ated with arsenic exposure (via water) can be most acute and
are well illustrated in a well-water problem for Bangladesh
(Murshed et al., 2004) Here water wells were established to
provide safe drinking-water sources (free of microbial
con-taminates) However, at the time these wells were placed it
was not known that the soil contained high levels of arsenic
This resulted in drinking-water sources being contaminated
with this metal Subsequently, there has been a high rate of
arsenic-related diseases (e.g., bladder, liver, and lung cancer;
Chen and Ahsan, 2004) as a direct result of using these water
sources Arsenic does not only result in cancer, it also causes
many environmentally related noncancer diseases (Milton
et al., 2003) As mentioned, there are also occupational
diseases from this metal (Bhamra and Costa, 1992; Lange,
2004a) For example, workers in smelting plants that use
arsenic have been shown to exhibit elevated levels of lung
cancer, and from these types of studies arsenic has been
identified as a lung carcinogen Although arsenic has been
reported to cause detrimental effects, it should be noted that
it is also an essential trace element Deficiency in arsenic has
been reported to result in various health problems as well as
increased mortality (Bhamra and Costa, 1992) Thus, many
chemicals can have a dual role in causing and preventing
disease It has even been suggested that some chemicals and
substances can have a protective effect in the occupational
environmental (Lange, 2000; Lange et al., 2003)
Chemicals can also be identified individually with a site
or organ system being affected Examples of chemicals and
their general site of action are shown in Table 5 Certainly
this list is not comprehensive, but provides the range of
organ systems a single chemical can influence in the disease
process Effects can be both acute and chronic along with many having both carcinogenic and noncarcinogenic proper-ties (e.g., benzene)
Excretion
Toxicants that are taken up by an organism must be eliminated
in some way There are three major routes of excretion (urine, feces, and air [exhalation]) and several minor routes (hair, nails, saliva, skin, milk, and sweat) Many compounds are biotrans-formed before being excreted This biotransformation results
in xenobiotics being more water-soluble As will be mentioned later, biotransformation involves a two-step process known as Phase I and Phase II biotransformation Generally, substances with the greatest toxicity are those that do not completely undergo the biotransformation process
Urinary excretion involves elimination through the kidney and is commonly considered the most important route of excretion The kidney receives about 25% of the cardiac output Toxic agents are generally excreted by being filtered out through the glomeruli or tubules in the kidney
Fecal excretion can involve both the GI tract and liverⲐ
gallbladder Some toxicants pass through the alimentary system (GI tract) unabsorbed or modified by bacteria or other processes in this system Biliary excretion involves removal
of toxicants from the blood by the liver and their subse-quent elimination through a fecal route Here a xenobiotic is
TABLE 4 Locations or organs of toxic action by classes of chemical compound
Class of Chemical/Substance Location or Organ (Example)
TABLE 5 Specific chemicals and some of their general organs or sites of action
Chemical Location or Organ (Example)
nervous
“Heart” includes the vascular system as a general group
Trang 7biotransformed by the lever and transported to the
gallblad-der, which then excretes the chemical into the GI tract for
elimination There are some cases where a chemical
elimi-nated by this route is then reabsorbed by the intestine into
the body, resulting in a long half-life for this substance This
process is known as the “enterohepatic cycle.” Ideally
chemi-cals are metabolized into a polar form, making these poorly
reabsorbable However, microbes in the intestine can
trans-form these compounds into a more lipid-soluble compound,
which favors reabsorption
Exhalation
Substances that exists in a gas phase are mostly eliminated
through the lungs These chemicals are mostly eliminated
through simple diffusion, with elimination generally related
to the inverse proportion of their rate of absorption Thus,
chemicals with low blood-solubility are rapidly eliminated,
while others with high solubility are eliminated slowly
Other Routes
Several other routes of excretion have been mentioned
Overall, these other routes are of minor importance in
elim-ination of toxicants However, they can be used to test the
existence and concentration of various toxicants in the
organ-ism This is commonly known as “biological monitoring.” For
example, hair can be used to test where a person has suffered
from previous exposure to and possible toxicity of heavy
metals, like arsenic Thus, these minor excretion routes can
be important for specific areas of toxicology (e.g., forensic)
It should be noted that the major routes can also be used for
biological monitoring, with urine and blood being the most
important, particularly clinically and occupationally
Biological Monitoring
Biological monitoring has become a common method for
evaluating absorption of chemicals and drugs It has been used
for such activities as drug and alcohol testing Methods have
been established to determine the absorbed dose of a
chemi-cal, which are therefore important in many areas of
toxicol-ogy, including clinical, forensic, and occupational toxicology
The ACGIH has established BEI values for some chemicals
as one measure of monitoring risk to industrial populations
This allows evaluation of exposure from all routes, including
occupational and nonoccupational In many cases, only one
route of exposure is evaluated, airborne levels, while exposure
from other routes (e.g., dermal) contributes to the absorbed
and toxic dose Biological monitoring can be used for both
major and minor routes of excretion As noted, hair and nails
can be used to evaluate exposure to heavy metals An
exam-ple of biological monitoring in the occupational environment
is for methyl ketone (MEK), which has been suggested to be
measured at the end of a work shift using urine as the
biologi-cal fluid The ACGIH BEI for MEK is 2 mgⲐl
Biological monitoring is also used as part of
medi-cal evaluations and in environmental toxicology as well
A good example of its use in medical evaluations is for lead-abatement workers Blood lead levels (BLL) for workers in this industry or exposure category have been established by OSHA Here workers having a BLL over 40 gⲐdl (deciliter
of whole blood—100 ml of blood) are required to undergo
an annual medical examination Workers over 50 gⲐdl are
required to be removed from the work area (removal from exposure) until the BLL (two connective readings) is below
40 gⲐdl This illustrates the use of biological monitoring
in prevention of occupational disease and its incorporation
in regulatory toxicology
Environmentally, lead is often monitored in children since it can cause harm in a number of organ systems and with effects that are characterized with a developing organ-ism The Centers for Disease Control and Prevention (CDC) suggest that children below the age of 6 not have a BLL that exceeds 10 gⲐdl This is the lowest level that has been
suggested to have biological effects for humans Biological concentrations of chemicals have also been used to evaluate exposure and toxic effects in organisms other than man
Monitoring of biological fluids and tissue in environmen-tal toxicology is a common practice (Pip and Mesa, 2002)
Both plants (Pip and Mesa, 2002) and animals (Madenjian and O’Connor, 2004) are used for evaluating the distribu-tion and uptake of toxicants from polluted environments
Monitoring can also be extended to abiotic conditions that influence toxicity to organisms (Mendez et al., 2004)
The use of biological systems for monitoring can include effects on metabolism and other systems as well (Lange and Thomulka, 1996) Thus, biological monitoring is commonly used in both environmental and occupational settings as well
as other areas of toxicology Monitoring of this nature has even been extended to ecosystems as a methodology for evaluating health
Biotransformation
Xenobiotic substances that are taken up by an organism must eventually be eliminated To eliminate many of these chemicals, they must be transformed into a water-soluble product This transformation is called “biotransformation.”
In many vertebrates, this transformation occurs in the liver, although other tissues and organs (e.g., the kidney) are also involved Generally, chemicals are absorbed as lipid pounds and excreted as water-soluble (hydrophilic) com-pounds Hydrophilic compounds can be easily passed along with the urine and feces In the lungs, volatile compounds are favored for excretion in the exhaled gas, while those that are nonvolatile are generally retained If chemicals were not biotransformed, their rate of excretion as lipid-soluble com-pounds would be very long, and this would result in buildup
of xenobiotics The rate at which a chemical is metabolized
or excreted is called its half-life ( t 1Ⲑ2 ) Half-lives can be very short (as in minutes) or long (as in years)
Biotransformation and metabolism are often used as
synonymous terms In general they can be used
interchange-ably, although here biotransformation is used in describing
the metabolism of xenobiotics that are not part of normal
Trang 8metabolism or at concentrations related to pollutant or
toxi-cant exposure
Some chemicals are able to actually increase or stimulate
the biotransformation of other compounds This is known as
“induction.” Induction can occur for a variety of compounds
As previously mentioned, biotransformation is generally
divided into two categories, Phase I and Phase II Phase I
reactions involve oxidation, reduction, and hydrolysis, which
prepare the compound to undergo a Phase II reaction Phase II
involves conjugation Commonly the most toxic products of
a chemical are those from Phase I If the system becomes
saturated, Phase I compounds will seek alternative routes of
metabolism, and this may result in more toxic intermediates
If this occurs, it is said that the metabolic system has become
saturated
MIXTURE TOXICITY
Most toxicology studies involve the use of a single
com-pound; however, rarely in the real world does exposure occur
to only a single substance Although single-exposure events
do occur, they generally result in acute toxicity, while
mul-tiple exposures are more frequently associated with chronic
events Certainly there are numerous exceptions to this rule,
like asbestos and mesothelioma, but even with asbestos there
are mixtures associated with this substance One of the best
illustrations for a mixture is asbestos and smoking in the case
of lung cancer Here smoking magnifies the potential effect of
inhaled asbestos, resulting in a higher-than-expected rate of
lung cancer than would occur for either alone Most exposures
in the industrial environmental focus on a single predominant
toxicant associated with that activity, or at the most the top
two or three chemicals, and generally concerns are identified
with acute events Both PEL and TLV are established with
nonexposure time periods between exposures and often have
an emphasis on acute occurrences In environmental
toxicol-ogy this is not always the case, since most regulatory
stan-dards have been established to protect against chronic events,
considering most organisms spend their entire life in a single
media This is also true for humans as related to air and water
pollution
Mixture toxicity or interaction studies can be generally
categorized by several terms (Table 6) Additivity is when two
chemicals together exhibit equal toxicity with each having the
same additive response So if chemicals A and B were mixed
and have an effect of ten, by adding five units of each, than
adding ten units of A alone or B alone would have the effect
of ten as well Synergism is where the combination of the two
chemicals magnify the outcome, as in asbestos and smoking
Asbestos may cause 1 cancer in 1000 and smoking 200 cases
in 1000, but when together this may rise to 700 cases out of
1000 Antagonism is when one chemical reduces the effect caused when combined with another Potentiation is when one
chemical allows another to have its full toxic potential This can be illustrated when the barrier of the skin is disrupted, as with DMSO, and a chemical that would not previously pass through the skin now enters easily Generally, most chemical combinations exhibit additivity
Unfortunately, little information exists on chemical com-binations (Lange and Thomulka, 1997) The lack of informa-tion is often due to the complexity and costs associated with these studies However, recent advances in using bacterial systems (Lange and Thomulka, 1997) for evaluating mix-tures does provide a more cost-effective and convenient way
of testing more than one chemical
There have been a number of methods published, exclud-ing statistical comparisons, for evaluatexclud-ing two chemicals in combination One of the early methods was a graphic repre-sentation of the two chemicals together, called an “isobole plot” (Lange and Thomulka, 1997) Here chemical combina-tions at some set value (like each chemical’s LD 50 ) are plot-ted Usually combinations of 100% of A, 80(A)Ⲑ20(B)%,
60Ⲑ40%, 20Ⲑ80%, and 100% of B are used in making the
plot When this graph is represented in proportions, it is called an isobologram (Lange et al., 1997)
Another method that employs a formula is called the additive index (AI) (Lange and Thomulka, 1997) Here two chemicals using the same endpoint value (like LD 50 ) are evaluated, and these results are incorporated into the formula
to obtain the AI The AI is shown below:
S ⫽ A m ⲐA i ⫹ B m ⲐB i
S is sum of activity
A and B are chemicals
i is individual chemical and m is mixture of toxicities
(LD 50 )
for S 1.0, the AI ⫽ 1Ⲑ S ⫺ 1.0
for S 1.0, the AI ⫽ S (⫺1) ⫹ 1
For the AI, a negative number (sum of activity, S ) suggests
that the chemicals are less than additive (antagonistic), with zero being additive and a positive value synergistic Certainly
in these calculations the numbers are not exact, so confidence intervals (CIs) are often incorporated to reflect the range of these mixture interactions In using CI values, at 95%, the upper and lower CIs are used to determine the range If the
CI range includes zero, then this mixture is considered to be additive
Mixture toxicity is a commonly discussed topic, but as mentioned, it is not well understood One basis for syner-gism is related to inhibition of detoxification pathways;
however, as noted, most chemical mixtures are additive,
TABLE 6 Terms used for identifying mixture interactions Term Example by Numerical Value
Trang 9which is probably due to few chemicals, at least in mixtures,
using exactly the same metabolic pathways Other
meth-ods exist for evaluating mixtures (e.g., the mixture-toxicity
index; Lange et al., 1997) Determination of interactions for
more than one chemical can in many ways be identified as
an art (Marking, 1985) However, as science develops, better
methods are being developed to evaluate combinations
CARCINOGENICITY
The existence of cancer-causing chemicals has been known
for thousands of years However, it was not until recently
that a direct relationship between environment or
occupa-tion and cancer was established One of the early examples
of an occupational relationship was provided by the English
physician Percival Pott around 1775 Pott observed a high
number of cases of scrotum cancer in chimney sweeps He
concluded that this cancer was a result of soot exposure
in this occupational group Later Japanese investigators
(Yamagawa and Ichikawa, 1915) determined that coal tar
(a common component of which is polyaromatic
hydrocar-bons), a component in soot, exhibited carcinogenic effects
on animals, providing a basic animal model to support the
occupational observations of Pott
Cancer in its simplest term is the unregulated or
uncon-trolled growth of cells in an organism Cancer, or neoplasm,
can be either benign or malignant Those that are benign
generally occupy a given space and do not spread to other
parts of the body If the cancer is said to be malignant, it is
then metastatic and can spread and form secondary sites at
various other locations within the body
Probably the best-known cancer-causing agent is
ciga-rette smoke Studies have shown that direct and indirect use
of this product can result in cancer Doll and Hill (1954)
demonstrated that cigarette smoking was a major cause of
lung cancer Although this was an epidemiological study,
these types of investigations opened up a new era of
investi-gation into cancer-causing agents
A cancer-causing agent generally has two processes in
the causation of a tumor: initiation and promotion This has
resulted in chemicals being identified as either initiators or
promoters, although there are some, known as “complete
carcinogens,” that exhibit both properties This concept was
developed by painting chemicals on the skin of mice at
dif-ferent time periods and observing whether tumor formation
occurred It was discovered that for some chemical
combi-nations, the initiator had to be applied before the promoter
When the promoter was applied first, a time period waited,
and then the initiator applied, no tumor formation occurred
Cancer can also be caused by other nonchemical factors such
as heredity and viruses
There has been considerable debate as to the amount of
cancer caused by environmental pollutants and exposures in
the occupational environment However, it is known that there
are a large number of agents capable of causing cancer in both
the environmental and occupational settings A list of a few
occupationally associated carcinogens is shown in Table 7
This list is not complete but demonstrates the large variety and locations of cancers Most environmental engineers look
at the agents capable of or identified as causing cancer when evaluating a situation; however, this is usually done for sim-plicity, in that cancer is an endpoint of clarity—it exists or
it does not exist It must be kept in mind that there are other endpoints of interest as well that are noncarcinogenic (e.g., kidney toxicity)
To classify carcinogens, several agencies list chemi-cals or substances according to their degree of carcino-genicity One of the most frequently cited agencies is the International Agency for Research on Cancer (IARC) The IARC is located in Lyon, France, and is part of the World Health Organization As part of this agency’s charter, it pub-lishes monographs for various substances and is considered
by many an excellent reference on information on carcino-gens This agency classifies cancer-causing agents into five different groups (Table 8) These grouping are based on data from epidemiological and animal studies Many consider the IARC to be the best source of information and classification for carcinogens
Group 1 indicates that there is sufficient epidemiological data that the substance is a human carcinogen This is the highest level of classification, and as noted in Table 8, an example is arsenic Group 2 has two classifications, A and B
Group 2A represents limited epidemiological evidence but sufficient animal evidence that the substance is a carcino-gen, while with group 2B there is sufficient animal evidence, but epidemiological data are lacking or of poor quality With Group 3 there is inadequate evidence for classifying a chem-ical or substance as a carcinogen Group 4 evidence supports that it is not a carcinogen
The IARC is not the only agency that classifies carcinogens
The National Toxicity Program (NTP) provides a classification scheme Here carcinogens are listed as known human carcino-gens or as reasonably anticipated to be a human carcinogen
TABLE 7 Some carcinogenic chemicals (substances) and the cancers
they cause
Trang 10For a chemical to be classified as a known human carcinogen
there must be sufficient evidence to support a causal
relation-ship between its exposure and the occurrence of human cancer
For substances to be listed as an anticipated human carcinogen
there must exist sufficient evidence that it is a carcinogen, but
alternative explanations exist or there is insufficient evidence
supporting classification, experimentally and
epidemiologi-cally, as a carcinogen
Regardless of the classification used, evidence of
car-cinogenicity for a substance requires epidemiological and
experimental evidence Epidemiological information is
con-sidered to be the strongest in establishing a substance as a
carcinogen
REGULATORY TOXICOLOGY
Regulatory toxicology is the area that interrelates
toxicol-ogy with regulatory standards The purpose of this area is to
establish standards to provide protection against a specific
chemical or group of chemicals In many cases, standards are
established before the full knowledge of a chemical is
com-plete Some identify this type of decision making to be part
of risk assessment In the United States, regulations related to
toxicology can be generally divided into the major agencies
that promulgate criteria for chemicals These are the Food and
Drug Administration (FDA), the Environmental Protection
Agency (EPA), OSHA, MSHA, and the Consumer Product
Safety Commission (CPSC) There are other agencies (e.g.,
the Department of Transportation), but for the purposes of
this section they are considered minor The agencies that are
important for environmental engineers are the EPA and OSHA
However, those with the mining industry will also consider
MSHA of great importance The EPA, in general, establishes
standards for environmental protection, and OSHA for
protec-tion related to those in the occupaprotec-tional environment For
con-sumer substances and products, the CPSC regulates toxicity
OSHA came into existence with the passage of the
Occupational Safety and Health Act on December 29, 1970
(effective April 28, 1971) OSHA as well as MSHA are part
of the U.S Department of Labor OSHA has five major parts, with each regulating different industrial groups (Table 9)
The OSHA act sets out two primary duties for employers, which are for them to maintain a workplace free of recognized hazards and to comply with OSHA regulations The act also requires that employees comply with the act, although clari-fication of this requirement is often lacking Requirements of the employer are called the General Duty Clause States can have their own OSHA plan and enforce OSHA as a state pro-vision if they meet certain requirements Currently, there are
23 state plans
Commonly, environmental engineers will be required
to interact with OSHA inspectors OSHA often conducts inspections as a random process, or more frequently does
so as a result of complaint When an inspection occurs, the inspector will present identification to the management of the facility If a labor union exists, the inspector must also notify the labor-union representative Usually there is then
an examination of the OSHA records, usually materials safety data sheets (MSDS) and the OSHA 200 form Lack
of MSDS, which is part of the Hazard Communication Plan, is one of the most frequently cited violations A walkthrough is then conducted, which may include the collection of samples At the end of this process there is
a closing conference At this time alleged violations are discussed If citations are issued they can consist of one of three types: imminent danger, serious violations, and will-ful violations
Employers can contest citations This is usually initiated through an informal hearing If the employer then decides
to contest the citation, there is a specific process that must
be undertaken OSHA has an independent review commis-sion as part of the Department of Labor to hear contested citations To contest the citation, the employer must file notice within 15 working days by certified mail There is
TABLE 8 IARC classification groups for carcinogenic substances
Group 1: Carcinogenic to humans (common called “known”) carcinogen
(examples: asbestos, arsenic) (evidence supports the chemical or
substance as a human carcinogen)
Group 2A: Probably carcinogenic to humans (examples: diethyl sulfate,
vinyl bromide) (limited evidence in humans and sufficient evidence in
experimental animals)
Group 2B: Possibly carcinogenic to humans (examples: bracken fern,
chlordane) (limited evidence in humans and less than sufficient
evidence in experimental animals)
Group 3: Unclassified or not classified as carcinogenic to humans
(examples: aldrin, aniline) (inadequate evidence in humans and
inadequate or limited evidence in animals)
Group 4: Probably not carcinogenic to humans (example: caprolactam)
(evidence suggesting lack of carcinogenicity in humans and animals)
TABLE 9 Sections of the CFR related to OSHA standards
29 CFR 1910—General industry
29 CFR 1915—Shipyards
29 CFR 1917—Marine terminals
29 CFR 1918—Longshoring
29 CFR 126—Construction
TABLE 10 Some environmental acts of importance
Clear Air Act Clean Water Act Toxic Substance Control Act Resource Conservation and Recovery Act National Environmental Policy Act Comprehensive Environmental Response, Compensation, and Liability Act Emergency Planning and Right to Know Act