Multiple chemical sensitivity

From Wikipedia, the free encyclopedia

 

Multiple chemical sensitivity (MCS), also known as idiopathic environmental intolerances (IEI), is a disputed chronic condition characterized by symptoms that the affected person attributes to low-level exposures to commonly used chemicals. Symptoms are typically vague and non-specific. They may include fatigue, headaches, nausea, and dizziness.

Commonly attributed substances include scented products, pesticides, plastics, synthetic fabrics, smoke, petroleum products, and paint fumes.

Although the symptoms themselves are real, and can be disabling, MCS is not recognized as an organic, chemical-caused illness by the World Health Organization, American Medical Association, or any of several other professional medical organizations. Blinded clinical trials show that people with MCS react as often and as strongly to placebos as they do to chemical stimuli; the existence and severity of symptoms is related to perception that a chemical stimulus is present. Some attribute the symptoms to depression, somatoform disorders, or anxiety disorders.

Signs and symptoms

Symptoms range in severity from mild to disabling.

Symptoms are common, but vague and non-specific for the condition. The most common are feeling tired, "brain fog" (short-term memory problems, difficulty concentrating), gastrointestinal problems, headaches, and muscle pain.

A partial list of other symptoms patients have attributed to MCS include: difficulty breathing, pains in the throat, chest, or abdominal region, skin irritation, headaches, neurological symptoms (nerve pain, pins and needles feelings, weakness, trembling, restless leg syndrome), tendonitis, seizures, visual disturbances (blurring, halo effect, inability to focus), anxiety, panic and/or anger, sleep disturbance, suppression of immune system, digestive difficulties, nausea, indigestion/heartburn, vomiting, diarrhea, joint pains, vertigo/dizziness, abnormally acute sense of smell (hyperosmia), sensitivity to natural plant fragrance or natural pine terpenes, dry mouth, dry eyes, and an overactive bladder.

Causes

There is no clear consensus for the cause or causes of the symptoms of MCS. A 2007 National Institute of Environmental Health Sciences paper defined MCS as a "chronic, recurring disease caused by a person's inability to tolerate an environmental chemical or class of foreign chemicals".

In addition to extreme sensitivity to low concentrations of certain chemicals, several hypotheses have been proposed. The distinction between physiological and psychological causes is often difficult to test, and it is particularly challenging for MCS because many substances used to test for sensitivity have a strong odor. Odor cues make double blind studies of MCS patients difficult, as scents can provoke a psychosomatic response or recall expectations and prior beliefs. People with an MCS diagnosis show no differences in symptom severity, blood pressure, or heart rate when exposed to clean air or to solvents at a concentration too low to smell.

Chemical triggers

Many chemicals have been reported to trigger MCS symptoms. Substances with strong scents are the most commonly reported triggers. These include a variety of cleaning agents, pesticides, perfumes, vehicle exhaust, the products used in barber shops and beauty salons, new carpeting, new furniture, chlorine and fluoride in drinking water, fresh ink, and less commonly wood smoke and secondhand tobacco smoke. Food items reported as triggers include tartrazine (a.k.a. FD&C Yellow #5 or E102), and other azo dyes (in the absence of an allergy), caffeine, and monosodium glutamate.

Immune

One proposed hypothesis for the cause of multiple chemical sensitivity is immune system dysfunction after being sensitized by a chemical exposure.

Psychological

Several mechanisms for a psychological etiology have been proposed, including theories based on misdiagnoses of an underlying mental illness, stress, or classical conditioning. Many people with MCS meet the criteria for major depressive disorder or anxiety disorder. Other proposed explanations include somatoform disorder, panic disorder, migraine, chronic fatigue syndrome, or fibromyalgia, where symptoms such as brain fog and headaches can be triggered by chemicals or inhalants. Through behavioral conditioning, they may develop real, but unintentionally psychologically produced, symptoms such as anticipatory nausea when they encounter certain odors or other perceived triggers. Affected individuals may also have a tendency to "catastrophically misinterpret benign physical symptoms" or simply have a disturbingly acute sense of smell. The personality trait absorption, in which individuals are predisposed to becoming deeply immersed in sensory experiences, may be stronger in individuals reporting symptoms of MCS. Behaviors exhibited by MCS sufferers may reflect broader sociological fears about industrial pollution and broader societal trends of technophobia and chemophobia.

Neurological

People who suffer from MCS may have a neurological dysfunction in the odor-processing areas of the brain or may respond strongly to fumes or scents for some other reason.

Genetic differences in metabolism

Genetic differences relating to toxicant metabolism pathways, such as polymorphisms and differences in expression in CYP2D6, NAT2, GSTM1, and PON1 and PON2, have been proposed as a cause for differences in susceptibility to MCS. Elevated nitric oxide and peroxynitrite (NO/ONOO-) could then cause the symptoms of MCS and several related conditions, including fibromyalgia, posttraumatic stress disorder, Gulf War syndrome, and chronic fatigue syndrome.

Gulf War syndrome

People with British Gulf War syndrome who used personal organophosphate pesticides may be more likely to report the symptoms of MCS.

Diagnosis

No characteristically unique signs, laboratory test abnormalities, tissue pathology, or course of illness have been identified, and it remains unclear whether symptoms are physiologically or psychologically generated.

International Classification of Diseases

The International Statistical Classification of Diseases and Related Health Problems (ICD), maintained by the World Health Organization, does not recognize multiple chemical sensitivity or environmental sensitivity as a valid diagnosis. The Australian Department of Health recognizes that sometimes debilitating symptoms are attributed to MCS but notes that diagnosis, treatment, and any underlying mechanism remain uncertain. The German Institute for Medical Documentation and Information recognizes MCS as a physical disease and is subsequentially recognized in Austria. The American Medical Association does not recognize MCS as an organic disease because of the lack of scientific evidence supporting a cause-and-effect relationship between very low level exposure and the symptoms of MCS. The American Academy of Allergy, Asthma, and Immunology, the California Medical Association, the American College of Physicians, and the International Society of Regulatory Toxicology and Pharmacology also do not recognize MCS. The US Occupational Safety and Health Administration (OSHA) indicates that MCS is highly controversial and that there is insufficient scientific evidence to explain the relationship between the suggested causes of MCS and its symptoms. OSHA recommends evaluation by a physician knowledgeable of the symptoms presented.

Other

In response to a WHO call for papers at the 5th Paris Appeal Congress of Environmental Idiopathic Intolerance conference that took place in Belgium on 18 May 2015, a report that was generally supportive quoted a number of international practitioners. This was provisionally accepted by the Spanish health ministry, and later found proven by a judge in the case of a plumber in the Province of Castellón.

MCS is a diagnosis of exclusion, and the first step in diagnosing a potential MCS sufferer is to identify and treat all other conditions which are present and which often explain the reported symptoms. For example, depression, allergy, thyroid disorders, orthostatic syndromes, lupus, hypercalcemia, and anxiety need to be carefully evaluated and, if present, properly treated. The "gold standard" procedure for identifying a person who has MCS is to test response to the random introduction of chemicals the patient has self-identified as relevant. This may be done in a carefully designed challenge booth to eliminate the possibility of contaminants in the room. Chemicals and controls, sometimes called prompts, are introduced in a random method, usually scent-masked. The test subject does not know when a prompt is being given. Objective and subjective responses are measured. Objective measures, such as the galvanic skin response, indicate psychological arousal, such as fear, anxiety, or anger. Subjective responses include patient self-reports. A diagnosis of MCS can only be justified when the subject cannot consciously distinguish between chemicals and controls, and when responses are consistently present with exposure to chemicals and consistently absent when prompted by a control.

A 1999 consensus statement recommends that MCS be diagnosed according to six standardized criteria:

1. Symptoms are reproducible with repeated (chemical) exposures
2. The condition has persisted for a significant period of time
3. Low levels of exposure (lower than previously or commonly tolerated) result in manifestations of the syndrome (i.e. increased sensitivity)
4. The symptoms improve or resolve completely when the triggering chemicals are removed
5. Responses often occur to multiple chemically unrelated substances
6. Symptoms involve multiple-organ symptoms (runny nose, itchy eyes, headache, scratchy throat, ear ache, scalp pain, mental confusion or sleepiness, palpitations of the heart, upset stomach, nausea and/or diarrhea, abdominal cramping, aching joints).

Treatment

In various studies, about one half of the patients who seek medical treatment for symptoms of MCS meet the criteria for depressive and anxiety disorders. Because many people eliminate whole categories of food in an effort to reduce symptoms, a complete review of the patient's diet may be needed to avoid nutritional deficiencies.

Epidemiology

Epidemiological data from three states put the prevalence of chemical sensitivity in 1999 at 16 to 33% of the general population, 2 to 6% of whom have already been diagnosed with MCS.^[45] Women complain of MCS significantly more often than men, and most patients are 30 to 50 years old at time of diagnosis.

Gulf War syndrome

Several clinical and epidemiological studies conducted in the United States and in the United Kingdom have investigated the occurrence of MCS in military personnel deployed to the Persian Gulf during the 1990s. Some of the health complaints and symptoms reported by veterans of the Gulf War attributed to Gulf War syndrome are similar to those reported for MCS, including headache, fatigue, muscle stiffness, joint pain, inability to concentrate, sleep problems, and gastrointestinal issues.

A population-based, cross-sectional epidemiological study involving American veterans of the Gulf War, non-Gulf War veterans, and non-deployed reservists enlisted both during Gulf War era and outside the Gulf War era concluded the prevalence of MCS-type symptoms in Gulf War veterans was somewhat higher than in non-Gulf War veterans. After adjusting for potentially confounding factors (age, sex, and military training), there was a robust association between individuals with MCS-type symptoms and psychiatric treatment (either therapy or medication) before deployment and, therefore, before any possible deployment-connected chemical exposures.

The odds of reporting MCS or chronic multiple-symptom illness was 3.5 times greater for Gulf War veterans than non-Gulf veterans.

Gulf War veterans have an increased rate of multiple-symptom conditions compared to military personnel deployed to other conflicts, and although it is unexplained, Gulf War syndrome is not considered distinct from other medically unexplained syndromes observed in civilian populations, including MCS.

History

MCS was first proposed as a distinct disease by Theron G. Randolph in 1950. In 1965, Randolph founded the Society for Clinical Ecology as an organization to promote his ideas about symptoms reported by his patients. As a consequence, clinical ecology emerged as a non-recognized medical specialty. In 1984, the Society for Clinical Ecology changed its name to American Academy of Environmental Medicine (AAEM). In the 1990s, an association was noted with chronic fatigue syndrome, fibromyalgia, and Gulf War syndrome.

In 1994, the AMA, American Lung Association, US EPA and US Consumer Product Safety Commission published a booklet on indoor air pollution that discusses MCS, among other issues. The booklet further states that a pathogenesis of MCS has not been definitively proven, and that symptoms that have been self-diagnosed by a patient as related to MCS could actually be related to allergies or have a psychological basis, and recommends that physicians should counsel patients seeking relief from their symptoms that they may benefit from consultation with specialists in these fields.

In 1995, an Interagency Workgroup on Multiple Chemical Sensitivity was formed under the supervision of the Environmental Health Policy Committee within the United States Department of Health and Human Services to examine the body of research that had been conducted on MCS to that date. The work group included representatives from the Centers for Disease Control and Prevention, United States Environmental Protection Agency, United States Department of Energy, Agency for Toxic Substances and Disease Registry, and the National Institutes of Health. The Predecisional Draft document generated by the workgroup in 1998 recommended additional research in the basic epidemiology of MCS, the performance of case-comparison and challenge studies, and the development of a case definition for MCS. However, the workgroup also concluded that it was unlikely that MCS would receive extensive financial resources from federal agencies because of budgetary constraints and the allocation of funds to other, extensively overlapping syndromes with unknown cause, such as chronic fatigue syndrome, fibromyalgia, and Gulf War syndrome. The Environmental Health Policy Committee is currently inactive, and the workgroup document has not been finalized.

In 1997, U.S. Social Security Administration Commissioner John Callahan issued a court memorandum officially recognizing MCS "as a medically determinable impairment" on an agency-wide basis. That is, without making any statement about the cause of MCS or the role of chemicals in MCS, the Social Security administration agrees that some MCS patients are too disabled to be meaningfully employed.

A 1997 U.S. court decision held that MCS "is untested, speculative, and far from generally accepted in the medical or toxicological community," and thus cannot be used as the basis for disability claims. Furthermore, accommodations sought for MCS are sometimes denied as being unreasonable as a matter of law.

In July 2017, the Task Force on Environmental Health of the Ontario, Canada Ministry of Health and Long-Term Care issued a Phase 1 report, "Time for Leadership: Recognizing and Improving Care for those with ME/CFS, FM and ES/MCS", summarized in Canadian Family Physician  in June 2018 (v.64{6}; PMC5999262), "Recent Insights Into 3 Under-recognized Conditions: Myalgic Encephalomyelitis–Chronic Fatigue Syndrome, Fibromyalgia, and Environmental Sensitivities–Multiple Chemical Sensitivity". "[M]ounting evidence of biological mechanisms" is cited in the latter. In February 2018, the Journal of Occupational and Environmental Medicine (official publication of the American College of Occupational and Environmental Medicine) published "Multiple Chemical Sensitivity: Review of the State of the Art in Epidemiology, Diagnosis, and Future Perspectives" covering seventeen years of literature internationally on the topic.

Physiologically based pharmacokinetic modelling

From Wikipedia, the free encyclopedia

 

Graphic representation of a physiologically based whole body model. Here, it is dissected into seven tissue/organ compartments: brain, lungs and heart, pancreas, liver, gut, kidney and adipose/muscle tissue. Blood flows, Q, and concentration, [X], of a substance of interest are depicted.

Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique for predicting the absorption, distribution, metabolism and excretion (ADME) of synthetic or natural chemical substances in humans and other animal species. PBPK modeling is used in pharmaceutical research and drug development, and in health risk assessment for cosmetics or general chemicals.

PBPK models strive to be mechanistic by mathematically transcribing anatomical, physiological, physical, and chemical descriptions of the phenomena involved in the complex ADME processes. A large degree of residual simplification and empiricism is still present in those models, but they have an extended domain of applicability compared to that of classical, empirical function based, pharmacokinetic models. PBPK models may have purely predictive uses, but other uses, such as statistical inference, have been made possible by the development of Bayesian statistical tools able to deal with complex models. That is true for both toxicity risk assessment and therapeutic drug development.

PBPK models try to rely a priori on the anatomical and physiological structure of the body, and to a certain extent, on biochemistry. They are usually multi-compartment models, with compartments corresponding to predefined organs or tissues, with interconnections corresponding to blood or lymph flows (more rarely to diffusions). A system of differential equations for concentration or quantity of substance on each compartment can be written, and its parameters represent blood flows, pulmonary ventilation rate, organ volumes etc., for which information is available in scientific publications. Indeed, the description they make of the body is simplified and a balance needs to be struck between complexity and simplicity. Besides the advantage of allowing the recruitment of a priori information about parameter values, these models also facilitate inter-species transpositions or extrapolation from one mode of administration to another (e.g., inhalation to oral). An example of a 7-compartment PBPK model, suitable to describe the fate of many solvents in the mammalian body, is given in the Figure at the top.

History

The first pharmacokinetic model described in the scientific literature  was in fact a PBPK model. It led, however, to computations intractable at that time. The focus shifted then to simpler models, for which analytical solutions could be obtained (such solutions were sums of exponential terms, which led to further simplifications.) The availability of computers and numerical integration algorithms marked a renewed interest in physiological models in the early 1970s. For substances with complex kinetics, or when inter-species extrapolations were required, simple models were insufficient and research continued on physiological models. By 2010, hundreds of scientific publications have described and used PBPK models, and at least two private companies are basing their business on their expertise in this area.

Building a PBPK model

The model equations follow the principles of mass transport, fluid dynamics, and biochemistry in order to simulate the fate of a substance in the body . Compartments are usually defined by grouping organs or tissues with similar blood perfusion rate and lipid content (i.e. organs for which chemicals' concentration vs. time profiles will be similar). Ports of entry (lung, skin, intestinal tract...), ports of exit (kidney, liver...) and target organs for therapeutic effect or toxicity are often left separate. Bone can be excluded from the model if the substance of interest does not distribute to it. Connections between compartment follow physiology (e.g., blood flow in exit of the gut goes to liver, etc.)

Basic transport equations

Drug distribution into a tissue can be rate-limited by either perfusion or permeability. Perfusion-rate-limited kinetics apply when the tissue membranes present no barrier to diffusion. Blood flow, assuming that the drug is transported mainly by blood, as is often the case, is then the limiting factor to distribution in the various cells of the body. That is usually true for small lipophilic drugs. Under perfusion limitation, the instantaneous rate of entry for the quantity of drug in a compartment is simply equal to (blood) volumetric flow rate through the organ times the incoming blood concentration. In that case; for a generic compartment i, the differential equation for the quantity Q_i of substance, which defines the rate of change in this quantity, is:

${\displaystyle {dQ_{i} \over dt}=F_{i}(C_{art}-{{Q_{i}} \over {P_{i}V_{i}}})}$

where F_i is blood flow (noted Q in the Figure above), C_art incoming arterial blood concentration, P_i the tissue over blood partition coefficient and V_i the volume of compartment i.

A complete set of differential equations for the 7-compartment model shown above could therefore be given by the following table:

Tissue	Differential Equation
Gut	${\displaystyle {dQ_{g} \over dt}=F_{g}(C_{art}-{{Q_{g}} \over {P_{g}V_{g}}})}$
Kidney	${\displaystyle {dQ_{k} \over dt}=F_{k}(C_{art}-{{Q_{k}} \over {P_{k}V_{k}}})}$
Poorly-perfused tissues (muscle and skin)	${\displaystyle {dQ_{p} \over dt}=F_{p}(C_{art}-{{Q_{p}} \over {P_{p}V_{p}}})}$
Brain	${\displaystyle {dQ_{b} \over dt}=F_{b}(C_{art}-{{Q_{b}} \over {P_{b}V_{b}}})}$
Heart and lung	${\displaystyle {dQ_{h} \over dt}=F_{h}(C_{art}-{{Q_{h}} \over {P_{h}V_{h}}})}$
Pancreas	${\displaystyle {dQ_{pn} \over dt}=F_{pn}(C_{art}-{{Q_{pn}} \over {P_{pn}V_{pn}}})}$
Liver	${\displaystyle {dQ_{l} \over dt}=F_{a}C_{art}+F_{g}({{Q_{g}} \over {P_{g}V_{g}}})+F_{pn}({{Q_{pn}} \over {P_{pn}V_{pn}}})-(F_{a}+F_{g}+F_{pn})({{Q_{l}} \over {P_{l}V_{l}}})}$

The above equations include only transport terms and do not account for inputs or outputs. Those can be modeled with specific terms, as in the following.

Modeling inputs

Modeling inputs is necessary to come up with a meaningful description of a chemical's pharmacokinetics. The following examples show how to write the corresponding equations.

Ingestion

When dealing with an oral bolus dose (e.g. ingestion of a tablet), first order absorption is a very common assumption. In that case the gut equation is augmented with an input term, with an absorption rate constant K_a:

${\displaystyle {dQ_{g} \over dt}=F_{g}(C_{art}-{{Q_{g}} \over {P_{g}V_{g}}})+K_{a}Q_{ing}}$

That requires defining an equation for the quantity ingested and present in the gut lumen:

${\displaystyle {dQ_{ing} \over dt}=-K_{a}Q_{ing}}$

In the absence of a gut compartment, input can be made directly in the liver. However, in that case local metabolism in the gut may not be correctly described. The case of approximately continuous absorption (e.g. via drinking water) can be modeled by a zero-order absorption rate (here R_ing in units of mass over time):

${\displaystyle {dQ_{g} \over dt}=F_{g}(C_{art}-{{Q_{g}} \over {P_{g}V_{g}}})+R_{ing}}$

More sophisticated gut absorption model can be used. In those models, additional compartments describe the various sections of the gut lumen and tissue. Intestinal pH, transit times and presence of active transporters can be taken into account .

Skin depot

The absorption of a chemical deposited on skin can also be modeled using first order terms. It is best in that case to separate the skin from the other tissues, to further differentiate exposed skin and non-exposed skin, and differentiate viable skin (dermis and epidermis) from the stratum corneum (the actual skin upper layer exposed). This is the approach taken in [Bois F., Diaz Ochoa J.G. Gajewska M., Kovarich S., Mauch K., Paini A., Péry A., Sala Benito J.V., Teng S., Worth A., in press, Multiscale modelling approaches for assessing cosmetic ingredients safety, Toxicology. doi: 10.1016/j.tox.2016.05.026].

Unexposed stratum corneum simply exchanges with the underlying viable skin by diffusion:

${\displaystyle {dQ_{{sc}_{u}} \over dt}=K_{p}\times S_{s}\times (1-f_{S_{e}})\times ({Q_{s_{u}} \over {P_{sc}V_{{sc}_{u}}}}-C_{{sc}_{u}})}$

where ${\displaystyle K_{p}}$ is the partition coefficient, ${\displaystyle S_{s}}$ is the total skin surface area, ${\displaystyle f_{S_{e}}}$ the fraction of skin surface area exposed, ...

For the viable skin unexposed:

${\displaystyle {dQ_{s_{u}} \over dt}=F_{s}(1-f_{S_{e}})(C_{art}-{{Q_{s_{u}}} \over {P_{s}V_{s_{u}}}})-{dQ_{{sc}_{u}} \over dt}}$

For the skin stratum corneum exposed:

${\displaystyle {dQ_{{sc}_{e}} \over dt}=K_{p}\times S_{s}\times f_{S_{e}}\times ({Q_{s_{e}} \over {P_{sc}V_{{sc}_{e}}}}-C_{{sc}_{e}})}$

for the viable skin exposed:

${\displaystyle {dQ_{s_{e}} \over dt}=F_{s}f_{S_{e}}(C_{art}-{{Q_{s_{e}}} \over {P_{s}V_{s_{e}}}})-{dQ_{{sc}_{e}} \over dt}}$

dt(QSkin_u) and dt(QSkin_e) feed from arterial blood and back to venous blood.
More complex diffusion models have been published [reference to add].

Intra-venous injection

Intravenous injection is a common clinical route of administration. (to be completed)

Inhalation

Inhalation occurs through the lung and is hardly dissociable from exhalation (to be completed)

Modelling metabolism

There are several ways metabolism can be modeled. For some models, a linear excretion rate is preferred. This can be accomplished with a simple differential equation. Otherwise a Michaelis-Menten equation, as follows, is generally appropriate for a more accurate result.

${\displaystyle v={\frac {d[P]}{dt}}={\frac {V_{\max }{[S]}}{K_{m}+[S]}}}$.

Uses of PBPK modeling

Simulated drug plasma concentration over time curves following IV infusion and multiple oral doses. The drug has an elimination half-life of 4 hours, and an apparent volume of distribution of 10 liters.

PBPK models are compartmental models like many others, but they have a few advantages over so-called "classical" pharmacokinetic models, which are less grounded in physiology. PBPK models can first be used to abstract and eventually reconcile disparate data (from physicochemical or biochemical experiments, in vitro or in vivo pharmacological or toxicological experiments, etc.) They give also access to internal body concentrations of chemicals or their metabolites, and in particular at the site of their effects, be it therapeutic or toxic. Finally they also help interpolation and extrapolation of knowledge between:

• Doses: e.g., from the high concentrations typically used in laboratory experiments to those found in the environment
• Exposure duration: e.g., from continuous to discontinuous, or single to multiple exposures
• Routes of administration: e.g., from inhalation exposures to ingestion
• Species: e.g., transpositions from rodents to human, prior to giving a drug for the first time to subjects of a clinical trial, or when experiments on humans are deemed unethical, such as when the compound is toxic without therapeutic benefit
• Individuals: e.g., from males to females, from adults to children, from non-pregnant women to pregnant
• From in vitro to in vivo.

Some of these extrapolations are "parametric" : only changes in input or parameter values are needed to achieve the extrapolation (this is usually the case for dose and time extrapolations). Others are "nonparametric" in the sense that a change in the model structure itself is needed (e.g., when extrapolating to a pregnant female, equations for the foetus should be added).

Owing to the mechanistic basis of PBPK models, another potential use of PBPK modeling is hypothesis testing. For example, if a drug compound showed lower-than-expected oral bioavailability, various model structures (i.e., hypotheses) and parameter values can be evaluated to determine which models and/or parameters provide the best fit to the observed data. If the hypothesis that metabolism in the intestines was responsibility for the low bioavailability yielded the best fit, then the PBPK modeling results support this hypothesis over the other hypotheses evaluated.

As such, PBPK modeling can be used, inter alia, to evaluate the involvement of carrier-mediated transport, clearance saturation, enterohepatic recirculation of the parent compound, extra-hepatic/extra-gut elimination; higher in vivo solubility than predicted in vitro; drug-induced gastric emptying delays; gut loss and regional variation in gut absorption.

Limits and extensions of PBPK modeling

Each type of modeling technique has its strengths and limitations. PBPK modeling is no exception. One limitation is the potential for a large number of parameters, some of which may be correlated. This can lead to the issues of parameter identifiability and redundancy. However, it is possible (and commonly done) to model explicitly the correlations between parameters (for example, the non-linear relationships between age, body-mass, organ volumes and blood flows.

After numerical values are assigned to each PBPK model parameter, specialized or general computer software is typically used to numerically integrate a set of ordinary differential equations like those described above, in order to calculate the numerical value of each compartment at specified values of time (see Software). However, if such equations involve only linear functions of each compartmental value, or under limiting conditions (e.g., when input values remain very small) that guarantee such linearity is closely approximated, such equations may be solved analytically to yield explicit equations (or, under those limiting conditions, very accurate approximations) for the time-weighted average (TWA) value of each compartment as a function of the TWA value of each specified input.

PBPK models can rely on chemical property prediction models (QSAR models or predictive chemistry models) on one hand. For example, QSAR models can be used to estimate partition coefficients. They also extend into, but are not destined to supplant, systems biology models of metabolic pathways. They are also parallel to physiome models, but do not aim at modelling physiological functions beyond fluid circulation in detail. In fact the above four types of models can reinforce each other when integrated.
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PBPK models are data-hungry (many parameters need to be set) and may take a long time to develop and validate. For that reason, they have been criticized for delaying the development of important regulations.

Toxicity

From Wikipedia, the free encyclopedia

Toxicity
The skull and crossbones is a common symbol for toxicity.
Classification and external resources
ICD-10	T65.9

Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell (cytotoxicity) or an organ such as the liver (hepatotoxicity). By extension, the word may be metaphorically used to describe toxic effects on larger and more complex groups, such as the family unit or society at large. Sometimes the word is more or less synonymous with poisoning in everyday usage.

A central concept of toxicology is that the effects of a toxicant are dose-dependent; even water can lead to water intoxication when taken in too high a dose, whereas for even a very toxic substance such as snake venom there is a dose below which there is no detectable toxic effect. Toxicity is species-specific, making cross-species analysis problematic. Newer paradigms and metrics are evolving to bypass animal testing, while maintaining the concept of toxicity endpoints.

Types

There are generally four types of toxic entities; chemical, biological, physical and radiation:

• The R.M.Yassine Scale is the main scale used to measure toxicity.
• Chemical toxicants include inorganic substances such as, lead, mercury, hydrofluoric acid, and chlorine gas, and organic compounds such as methyl alcohol, most medications, and poisons from living things. While some weakly radioactive substances, such as uranium, are also chemical toxicants, more strongly radioactive materials like radium are not, their harmful effects (radiation poisoning) being caused by the ionizing radiation produced by the substance rather than chemical interactions with the substance itself.
• Disease-causing microorganisms and parasites are toxic in a broad sense, but are generally called pathogens rather than toxicants. The biological toxicity of pathogens can be difficult to measure because the "threshold dose" may be a single organism. Theoretically one virus, bacterium or worm can reproduce to cause a serious infection. However, in a host with an intact immune system the inherent toxicity of the organism is balanced by the host's ability to fight back; the effective toxicity is then a combination of both parts of the relationship. In some cases, e.g. cholera, the disease is chiefly caused by a nonliving substance secreted by the organism, rather than the organism itself. Such nonliving biological toxicants are generally called toxins if produced by a microorganism, plant, or fungus, and venoms if produced by an animal.
• Physical toxicants are substances that, due to their physical nature, interfere with biological processes. Examples include coal dust, asbestos fibers or finely divided silicon dioxide, all of which can ultimately be fatal if inhaled. Corrosive chemicals possess physical toxicity because they destroy tissues, but they're not directly poisonous unless they interfere directly with biological activity. Water can act as a physical toxicant if taken in extremely high doses because the concentration of vital ions decreases dramatically if there's too much water in the body. Asphyxiant gases can be considered physical toxicants because they act by displacing oxygen in the environment but they are inert, not chemically toxic gases.
• As already mentioned, radiation can have a toxic effect on organisms.

Measuring

Toxicity can be measured by its effects on the target (organism, organ, tissue or cell). Because individuals typically have different levels of response to the same dose of a toxic substance, a population-level measure of toxicity is often used which relates the probabilities of an outcome for a given individual in a population. One such measure is the LD₅₀. When such data does not exist, estimates are made by comparison to known similar toxic things, or to similar exposures in similar organisms. Then, "safety factors" are added to account for uncertainties in data and evaluation processes. For example, if a dose of a toxic substance is safe for a laboratory rat, one might assume that one tenth that dose would be safe for a human, allowing a safety factor of 10 to allow for interspecies differences between two mammals; if the data are from fish, one might use a factor of 100 to account for the greater difference between two chordate classes (fish and mammals). Similarly, an extra protection factor may be used for individuals believed to be more susceptible to toxic effects such as in pregnancy or with certain diseases. Or, a newly synthesized and previously unstudied chemical that is believed to be very similar in effect to another compound could be assigned an additional protection factor of 10 to account for possible differences in effects that are probably much smaller. Obviously, this approach is very approximate; but such protection factors are deliberately very conservative, and the method has been found to be useful in a deep variety of applications. 
Assessing all aspects of the toxicity of cancer-causing agents involves additional issues, since it is not certain if there is a minimal effective dose for carcinogens, or whether the risk is just too small to see. In addition, it is possible that a single cell transformed into a cancer cell is all it takes to develop the full effect (the "one hit" theory).

It is more difficult to determine the toxicity of chemical mixtures than a pure chemical, because each component displays its own toxicity, and components may interact to produce enhanced or diminished effects. Common mixtures include gasoline, cigarette smoke, and industrial waste. Even more complex are situations with more than one type of toxic entity, such as the discharge from a malfunctioning sewage treatment plant, with both chemical and biological agents.

The preclinical toxicity testing on various biological systems reveals the species-, organ- and dose- specific toxic effects of an investigational product. The toxicity of substances can be observed by (a) studying the accidental exposures to a substance (b) in vitro studies using cells/ cell lines (c) in vivo exposure on experimental animals. Toxicity tests are mostly used to examine specific adverse events or specific end points such as cancer, cardiotoxicity, and skin/eye irritation. Toxicity testing also helps calculate the No Observed Adverse Effect Level (NOAEL) dose and is helpful for clinical studies.

Classification

The international pictogram for toxic chemicals.

For substances to be regulated and handled appropriately they must be properly classified and labelled. Classification is determined by approved testing measures or calculations and have determined cut-off levels set by governments and scientists (for example, no-observed-adverse-effect levels, threshold limit values, and tolerable daily intake levels). Pesticides provide the example of well-established toxicity class systems and toxicity labels. While currently many countries have different regulations regarding the types of tests, numbers of tests and cut-off levels, the implementation of the Globally Harmonized System has begun unifying these countries.

Global classification looks at three areas: Physical Hazards (explosions and pyrotechnics), Health Hazards and environmental hazards.

Health hazards

The types of toxicities where substances may cause lethality to the entire body, lethality to specific organs, major/minor damage, or cause cancer. These are globally accepted definitions of what toxicity is. Anything falling outside of the definition cannot be classified as that type of toxicant.

Acute toxicity

Acute toxicity looks at lethal effects following oral, dermal or inhalation exposure. It is split into five categories of severity where Category 1 requires the least amount of exposure to be lethal and Category 5 requires the most exposure to be lethal. The table below shows the upper limits for each category.

Method of administration	Cat.1	Cat.2	Cat.3	Cat.4	Cat.5
Oral: LD50 measured in mg/kg of bodyweight	5	50	300	2000	5000
Dermal: LD50 measured in mg/kg of bodyweight	50	200	1000	2000	5000
Gas Inhalation: LC50 measured in ppmV	100	500	2500	20,000	Undefined
Vapour Inhalation: LC50 measured in mg/L	0.5	2.0	10	20	Undefined
Dust and Mist Inhalation: LC50 measured in mg/L	0.05	0.5	1.0	5.0	Undefined

Note: The undefined values are expected to be roughly equivalent to the category 5 values for oral and dermal administration.

Other methods of exposure and severity

Patch test

Skin corrosion and irritation are determined though a skin patch test analysis. This examines the severity of the damage done; when it is incurred and how long it remains; whether it is reversible and how many test subjects were affected.

Skin corrosion from a substance must penetrate through the epidermis into the dermis within four hours of application and must not reverse the damage within 14 days. Skin irritation shows damage less severe than corrosion if: the damage occurs within 72 hours of application; or for three consecutive days after application within a 14-day period; or causes inflammation which lasts for 14 days in two test subjects. Mild skin irritation minor damage (less severe than irritation) within 72 hours of application or for three consecutive days after application.

Serious eye damage involves tissue damage or degradation of vision which does not fully reverse in 21 days. Eye irritation involves changes to the eye which do fully reverse within 21 days.

Other categories

• Respiratory sensitizers cause breathing hypersensitivity when the substance is inhaled.
• A substance which is a skin sensitizer causes an allergic response from a dermal application.
• Carcinogens induce cancer, or increase the likelihood of cancer occurring.
• Reproductively toxic substances cause adverse effects in either sexual function or fertility to either a parent or the offspring.
• Specific-target organ toxins damage only specific organs.
• Aspiration hazards are solids or liquids which can cause damage through inhalation.

Environmental hazards

An Environmental hazard can be defined as any condition, process, or state adversely affecting the environment. These hazards can be physical or chemical, and present in air, water, and/or soil. These conditions can cause extensive harm to humans and other organisms within an ecosystem.

Common types of environmental hazards

• Water: detergents, fertilizer, raw sewage, prescription medication, pesticides, herbicides, heavy metals, PCBs
• Soil: heavy metals, herbicides, pesticides, PCBs
• Air: particulate matter, carbon monoxide, sulfur dioxide, nitrogen dioxide, asbestos, ground-level ozone, lead (from aircraft fuel, mining, and industrial processes)

The EPA maintains a list of priority pollutants for testing and regulation.

Occupational hazards

The expression "Mad as a hatter" and the "Mad Hatter" of the book Alice in Wonderland derive from the known occupational toxicity of hatters who used a toxic chemical for controlling the shape of hats.

Hazards in the arts

Hazards in the arts have been an issue for artists for centuries, even though the toxicity of their tools, methods, and materials was not always adequately realized. Lead and cadmium, among other toxic elements, were often incorporated into the names of artist's oil paints and pigments, for example "lead white" and "cadmium red."

20th century printmakers and other artists began to be aware of the toxic substances, toxic techniques, and toxic fumes in glues, painting mediums, pigments, and solvents, many of which in their labelling gave no indication of their toxicity. An example was the use of xylol for cleaning silk screens. Painters began to notice the dangers of breathing painting mediums and thinners such as turpentine. Aware of toxicants in studios and workshops, in 1998 printmaker Keith Howard published Non-Toxic Intaglio Printmaking which detailed twelve innovative Intaglio-type printmaking techniques including photo etching, digital imaging, acrylic-resist hand-etching methods, and introducing a new method of non-toxic lithography.

Mapping environmental hazards

There are many environmental health mapping tools. TOXMAP is a Geographic Information System (GIS) from the Division of Specialized Information Services of the United States National Library of Medicine (NLM) that uses maps of the United States to help users visually explore data from the United States Environmental Protection Agency's (EPA) Toxics Release Inventory and Superfund programs. TOXMAP is a resource funded by the US Federal Government. TOXMAP's chemical and environmental health information is taken from NLM's Toxicology Data Network (TOXNET) and PubMed, and from other authoritative sources.

Aquatic toxicity

Aquatic toxicity testing subjects key indicator species of fish or crustacea to certain concentrations of a substance in their environment to determine the lethality level. Fish are exposed for 96 hours while crustacea are exposed for 48 hours. While GHS does not define toxicity past 100 mg/l, the EPA currently lists aquatic toxicity as "practically non-toxic" in concentrations greater than 100 ppm.

Exposure	Category 1	Category 2	Category 3
Acute	≤ 1.0 mg/L	≤ 10 mg/L	≤ 100 mg/L
Chronic	≤ 1.0 mg/L	≤ 10 mg/L	≤ 100 mg/L

Note: A category 4 is established for chronic exposure, but simply contains any toxic substance which is mostly insoluble, or has no data for acute toxicity.

Factors influencing toxicity

Toxicity of a substance can be affected by many different factors, such as the pathway of administration (whether the toxicant is applied to the skin, ingested, inhaled, injected), the time of exposure (a brief encounter or long term), the number of exposures (a single dose or multiple doses over time), the physical form of the toxicant (solid, liquid, gas), the genetic makeup of an individual, an individual's overall health, and many others. Several of the terms used to describe these factors have been included here.

Acute exposure

A single exposure to a toxic substance which may result in severe biological harm or death; acute exposures are usually characterized as lasting no longer than a day.

Chronic exposure

Continuous exposure to a toxicant over an extended period of time, often measured in months or years; it can cause irreversible side effects.

Etymology

"Toxic" and similar words came from Greek τοξον = "bow (weapon)" via "poisoned arrow", which came to be used for "poison" in scientific language, as the usual Classical Greek word ('ιον) for "poison" would transliterate to "io-", which is not distinctive enough. In some biological names, "toxo-" still means "bow", as in Toxodon = "bow-toothed" from the shape.