Antimicrobial peptides

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Antimicrobial_peptides

Various structures of antimicrobial peptides

Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antimicrobials which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics it appears that antimicrobial peptides frequently destabilize biological membranes, can form transmembrane channels, and may also have the ability to enhance immunity by functioning as immunomodulators.

Structure

Antimicrobial peptides from animals, plants and fungi organised by their secondary structure content. Circle size indicates overall molecular weight of each peptide.

Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure. Antimicrobial peptides are generally between 12 and 50 amino acids. These peptides include two or more positively charged residues provided by arginine, lysine or, in acidic environments, histidine, and a large proportion (generally >50%) of hydrophobic residues. The secondary structures of these molecules follow 4 themes, including i) α-helical, ii) β-stranded due to the presence of 2 or more disulfide bonds, iii) β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain, and iv) extended. Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. The peptides contain hydrophilic amino acid residues aligned along one side and hydrophobic amino acid residues aligned along the opposite side of a helical molecule. This amphipathicity of the antimicrobial peptides allows them to partition into the membrane lipid bilayer. The ability to associate with membranes is a definitive feature of antimicrobial peptides, although membrane permeabilization is not necessary. These peptides have a variety of antimicrobial activities ranging from membrane permeabilization to action on a range of cytoplasmic targets.

Type	characteristic	AMPs
Anionic peptides	rich in glutamic and aspartic acids	Maximin H5 from amphibians, dermcidin from humans
Linear cationic α-helical peptides	lack in cysteine	Cecropins, andropin, moricin, ceratotoxin and melittin from insects, Magainin, dermaseptin, bombinin, brevinin-1, esculentins and buforin II from amphibians, CAP18 from rabbits, LL37 from humans
Cationic peptide enriched for specific amino acid	rich in proline, arginine, phenylalanine, glycine, tryptophan	abaecin and drosocin, apidaecin, diptericin, and attacin from insects, prophenin from pigs, indolicidin from cattle.
Anionic/cationic peptides forming disulfide bonds	contain 1~3 disulfide bond	1 bond: brevinins; 2 bonds: protegrin from pig, tachyplesins from horseshoe crabs; 3 bonds: defensins from humans; more than 3: drosomycin in fruit flies

Activities

The modes of action by Antimicrobial peptides

The modes of action by which antimicrobial peptides kill microbes are varied, and may differ for different bacterial species. Some antimicrobial peptides kill both bacteria and fungi, e.g., psoriasin kills E. coli and several filamentous fungi. The cytoplasmic membrane is a frequent target, but peptides may also interfere with DNA and protein synthesis, protein folding, and cell wall synthesis. The initial contact between the peptide and the target organism is electrostatic, as most bacterial surfaces are anionic, or hydrophobic, such as in the antimicrobial peptide Piscidin. Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores by ‘barrel-stave’, ‘carpet’ or ‘toroidal-pore’ mechanisms. Alternately, they may penetrate into the cell to bind intracellular molecules which are crucial to cell living. Intracellular binding models includes inhibition of cell wall synthesis, alteration of the cytoplasmic membrane, activation of autolysin, inhibition of DNA, RNA, and protein synthesis, and inhibition of certain enzymes. In many cases, the exact mechanism of killing is not known. One emerging technique for the study of such mechanisms is dual polarisation interferometry. In contrast to many conventional antibiotics these peptides appear to be bactericidal instead of bacteriostatic. In general the antimicrobial activity of these peptides is determined by measuring the minimal inhibitory concentration (MIC), which is the lowest concentration of drug that inhibits bacterial growth.

AMPs can possess multiple activities including anti-gram-positive bacterial, anti-gram-negative bacterial, anti-fungal, anti-viral, anti-parasitic, and anti cancer activities. A big AMP functional analysis indicates that among all AMP activities, amphipathicity and charge, two major properties of AMPs, best distinguish between AMPs with and without anti-gram-negative bacterial activities. This implies that being AMPs with anti-gram-negative bacterial activities may prefer or even require strong amphipathicity and net positive charge.

Immunomodulation

In addition to killing bacteria directly they have been demonstrated to have a number of immunomodulatory functions that may be involved in the clearance of infection, including the ability to alter host gene expression, act as chemokines and/or induce chemokine production, inhibiting lipopolysaccharide induced pro-inflammatory cytokine production, promoting wound healing, and modulating the responses of dendritic cells and cells of the adaptive immune response. Animal models indicate that host defense peptides are crucial for both prevention and clearance of infection. It appears as though many peptides initially isolated as and termed "antimicrobial peptides" have been shown to have more significant alternative functions in vivo (e.g. hepcidin). Dusquetide for example is an immunomodulator that acts through p62, a protein involved in toll like receptor based signalling of infection. The peptide is being examined in a Phase III clinical trial by Soligenix (SGNX) to ascertain if it can assist in repair of radiation-induced damage to oral mucosa arising during cancer radiotherapy of the head and neck.

Mechanisms of action

Scanning electron microscopic images (50,000X magnification) displaying the action of an experimental antimicrobial peptide (NN2_0050) on the cell membrane of E. coli (K12 MG1655)  ABOVE: Intact cell membranes in the control group. BELOW: Disrupted cell membranes and leakage of bacterial chromosome (green) in the treated group.

Antimicrobial peptides generally have a net positive charge, allowing them to interact with the negatively charged molecules exposed on bacteria and cancer cell surfaces, such as phospholipid phosphatidylserine, O-glycosylated mucins, sialylated gangliosides, and heparin sulfates. The mechanism of action of these peptides varies widely but can be simplified into two categories: membranolytic and non-membranolytic antimicrobial peptides. The disruption of membranes by membranolytic antimicrobial peptides can be described by four models:

• Barrel-stave model: The barrel-stave model proposes that AMPs interact with the lipid bilayer of the microbial cell membrane to form transmembrane channels or "barrel staves". These channels are thought to disrupt the membrane's integrity, leading to the death of the microbe.
• Carpet model: The carpet model proposes that AMPs adsorb onto the lipid bilayer of the microbial cell membrane, forming a dense layer that causes the membrane to become permeabilized. This model suggests that the AMP acts as a "carpet" that covers the surface of the cell, preventing the microbe from functioning properly.
• Toroidal model: The toroidal model proposes that AMPs interact with the lipid bilayer of the microbial cell membrane to form toroidal structures, which are thought to pinch off sections of the membrane and lead to the formation of vesicles. This process is thought to disrupt the membrane's integrity and cause the death of the microbe.
• Disordered toroidal-pore model: According to this model, the disordered AMPs wrap around the lipid bilayer and create a pore, which disrupts the membrane's integrity and leads to the death of the microbe. Unlike the toroidal model, which suggests that the AMP creates a stable toroidal structure, the disordered toroidal-pore model suggests that the AMP is flexible and does not form a stable toroidal structure. The peptide-lipid pore complex becomes intrinsically disordered, with the orientation of the peptide not well defined.^[21]

Schematic representation of the AMPs mechanisms of action when disrupting membranes.

Several methods have been used to determine the mechanisms of antimicrobial peptide activity. In particular, solid-state NMR studies have provided an atomic-level resolution explanation of membrane disruption by antimicrobial peptides. In more recent years, X-ray crystallography has been used to delineate in atomic detail how the family of plant defensins rupture membranes by identifying key phospholipids in the cell membranes of the pathogen. Human defensins have been thought to act through a similar mechanism, targeting cell membrane lipids as part of their function. In fact human beta-defensin 2 have now been shown to kill the pathogenic fungi Candida albicans through interactions with specific phospholipids. From the computational point of view, Molecular Dynamics simulations can provide detailed information about the structure and dynamics of the peptide-membrane interactions, including the orientation, conformation, and insertion of the peptide in the membrane, as well as specific peptide interactions with lipids, ions and solvent.

Methods	Applications
Microscopy	to visualize the effects of antimicrobial peptides on microbial cells
Atomic emission spectroscopy	to detect loss of intracellular potassium (an indication that bacterial membrane integrity has been compromised)
Fluorescent dyes	to measure ability of antimicrobial peptides to permeabilize membrane vesicles
Ion channel formation	to assess the formation and stability of an antimicrobial-peptide-induced pore
Circular dichroism and orientated circular dichroism	to measure the orientation and secondary structure of an antimicrobial peptide bound to a lipid bilayer
Dual polarization interferometry	to measure the different mechanisms of antimicrobial peptides
Solid-state NMR spectroscopy	to measure the secondary structure, orientation and penetration of antimicrobial peptides into lipid bilayers in the biologically relevant liquid-crystalline state
Neutron and X-ray diffraction	to measure the diffraction patterns of peptide-induced pores within membranes in oriented multilayers or liquids
Molecular dynamics simulations	to study the molecular behaviour and search for specific peptide-lipid interactions
Mass spectrometry	to measure the proteomic response of microorganisms to antimicrobial peptides

Therapeutic research and use

Antimicrobial peptides have been used as therapeutic agents; their use is generally limited to intravenous administration or topical applications due to their short half-lives. As of January 2018 the following antimicrobial peptides were in clinical use:

• Bacitracin for pneumonia, topical
• Boceprevir, Hepatitis C (oral, cyclic peptide)
• Dalbavancin, bacterial infections, IV
• Daptomycin, bacterial infections, IV
• Enfuvirtide, HIV, subcutaneous injection
• Oritavancin, bacterial infections, IV
• Teicoplanin, bacterial infections, IV
• Telaprevir, Hepatitis C, oral cyclic peptide
• Telavancin, bacterial infection, IV
• Vancomycin, bacterial infection, IV.
• Guavanin 2, bacterial infection against Gram-positive and Gram-negative also.

Activity beyond antibacterial functions

AMPs have been observed having functions other than bacterial and fungal killing. These activities include antiviral effects, but also roles in host defence such as anticancer functions and roles in neurology. This has led to a movement for re-branding AMPs as "Host-defence peptides" to encompass the broad scope of activities AMPs can have.

Anticancer properties

Some cecropins (e.g. cecropin A, and cecropin B) have anticancer properties and are called anticancer peptides (ACPs). Hybrid ACPs based on Cecropin A have been studied for anticancer properties. The fruit fly Defensin prevents tumour growth, suspected to bind to tumour cells owing to cell membrane modifications common to most cancer cells, such as phosphatidylserine exposure.

Antibiofilm properties

Cecropin A can destroy planktonic and sessile biofilm-forming uropathogenic E. coli (UPEC) cells, either alone or when combined with the antibiotic nalidixic acid, synergistically clearing infection in vivo (in the insect host Galleria mellonella) without off-target cytotoxicity. The multi-target mechanism of action involves outer membrane permeabilization followed by biofilm disruption triggered by the inhibition of efflux pump activity and interactions with extracellular and intracellular nucleic acids.

Other research

Recently there has been some research to identify potential antimicrobial peptides from prokaryotes, aquatic organisms such as fish, and shellfish, and monotremes such as echidnas.

Selectivity

In the competition of bacterial cells and host cells with the antimicrobial peptides, antimicrobial peptides will preferentially interact with the bacterial cell to the mammalian cells, which enables them to kill microorganisms without being significantly toxic to mammalian cells.

With regard to cancer cells, they themselves also secrete human antimicrobial peptides including defensin, and in some cases, they are reported to be more resistant than the surrounding normal cells. Therefore, we cannot conclude that selectivity is always high against cancer cells.

Factors

There are some factors that are closely related to the selectivity property of antimicrobial peptides, among which the cationic property contributes most. Since the surface of the bacterial membranes is more negatively charged than mammalian cells, antimicrobial peptides will show different affinities towards the bacterial membranes and mammalian cell membranes.

In addition, there are also other factors that will affect the selectivity. It's well known that cholesterol is normally widely distributed in the mammalian cell membranes as a membrane stabilizing agent but absent in bacterial cell membranes (except when sequestered by H. pylori); and the presence of these cholesterols will also generally reduce the activities of the antimicrobial peptides, due either to stabilization of the lipid bilayer or to interactions between cholesterol and the peptide. So the cholesterol in mammalian cells will protect the cells from attack by the antimicrobial peptides.

Besides, the transmembrane potential is well known to affect peptide-lipid interactions. There's an inside-negative transmembrane potential existing from the outer leaflet to the inner leaflet of the cell membranes and this inside-negative transmembrane potential will facilitate membrane permeabilization probably by facilitating the insertion of positively charged peptides into membranes. By comparison, the transmembrane potential of bacterial cells is more negative than that of normal mammalian cells, so bacterial membrane will be prone to be attacked by the positively charged antimicrobial peptides.

Similarly, it is also believed that increasing ionic strength, which in general reduces the activity of most antimicrobial peptides, contributes partially to the selectivity of the antimicrobial peptides by weakening the electrostatic interactions required for the initial interaction.

Molecular Basis of Cell Selectivity of Antimicrobial Peptides

Mechanism

The cell membranes of bacteria are rich in acidic phospholipids, such as phosphatidylglycerol and cardiolipin.

In contrast, the outer part of the membranes of plants and mammals is mainly composed of lipids without any net charges since most of the lipids with negatively charged headgroups are principally sequestered into the inner leaflet of the plasma membranes. Thus in the case of mammalian cells, the outer surfaces of the membranes are usually made of zwitterionic phosphatidylcholine and sphingomyelin, even though a small portion of the membrane's outer surfaces contain some negatively charged gangliosides. Therefore, the hydrophobic interaction between the hydrophobic face of amphipathic antimicrobial peptides and the zwitterionic phospholipids on the cell surface of mammalian cell membranes plays a major role in the formation of peptide-cell binding.

Dual polarisation interferometry has been used in vitro to study and quantify the association to headgroup, insertion into the bilayer, pore formation and eventual disruption of the membrane.

Control

A lot of effort has been put into controlling cell selectivity. For example, attempts have been made to modify and optimize the physicochemical parameters of the peptides to control the selectivities, including net charge, helicity, hydrophobicity per residue (H), hydrophobic moment (μ) and the angle subtended by the positively charged polar helix face (Φ). Other mechanisms like the introduction of D-amino acids and fluorinated amino acids in the hydrophobic phase are believed to break the secondary structure and thus reduce hydrophobic interaction with mammalian cells. It has also been found that Pro→Nlys substitution in Pro-containing β-turn antimicrobial peptides was a promising strategy for the design of new small bacterial cell-selective antimicrobial peptides with intracellular mechanisms of action. It has been suggested that direct attachment of magainin to the substrate surface decreased nonspecific cell binding and led to improved detection limit for bacterial cells such as Salmonella and E. coli.

Bacterial resistance

Bacteria use various resistance strategies to avoid antimicrobial peptide killing.

• Some microorganisms alter net surface charges. Staphylococcus aureus transports D-alanine from the cytoplasm to the surface teichoic acid which reduces the net negative charge by introducing basic amino groups. S. aureus also modifies its anionic membranes via MprF with L-lysine, increasing the positive net charge.
• The interaction of antimicrobial peptides with membrane targets can be limited by capsule polysaccharide of Klebsiella pneumoniae.
• Salmonella species reduce the fluidity of their outer membrane by increasing hydrophobic interactions between an increased number of Lipid A acyl tails by adding myristate to Lipid A with 2-hydroxymyristate and forming hepta-acylated Lipid A by adding palmitate. The increased hydrophobic moment is thought to retard or abolish antimicrobial peptide insertion and pore formation. The residues undergo alteration in membrane proteins. In some Gram-negative bacteria, alteration in the production of outer membrane proteins correlates with resistance to killing by antimicrobial peptides.
• Non-typeable Hemophilus influenzae transports AMPs into the interior of the cell, where they are degraded. Furthermore, H. influenzae remodels its membranes to make it appear as if the bacterium has already been successfully attacked by AMPs, protecting it from being attacked by more AMPs.
• ATP-binding cassette transporters import antimicrobial peptides and the resistance-nodulation cell-division efflux pump exports antimicrobial peptides. Both transporters have been associated with antimicrobial peptide resistance
• Bacteria produce proteolytic enzymes, which may degrade antimicrobial peptides leading to their resistance.
• Outer membrane vesicles produced by Gram-negative bacteria bind the antimicrobial peptides and sequester them away from the cells, thereby protecting the cells. The outer membrane vesicles are also known to contain various proteases, peptidases and other lytic enzymes, which may have a role in degrading the extracellular peptide and nucleic acid molecules, which if allowed to reach to the bacterial cells may be dangerous for the cells.
• Cyclic-di-GMP signaling had also been involved in the regulation of antimicrobial peptide resistance in Pseudomonas aeruginosa

While these examples show that resistance can evolve naturally, there is increasing concern that using pharmaceutical copies of antimicrobial peptides can make resistance happen more often and faster. In some cases, resistance to these peptides used as a pharmaceutical to treat medical problems can lead to resistance, not only to the medical application of the peptides, but to the physiological function of those peptides.

The ‘Trojan Horse’ approach to solving this problem capitalizes on the innate need for iron by pathogens. “Smuggling” antimicrobials into the pathogen is accomplished by linking them to siderophores for transport. While simple in concept, it has taken many decades of work to accomplish the difficult hurdle of transporting antimicrobials across the cell membranes of pathogens. Lessons learned from the successes and failures of siderophore-conjugate drugs evaluated during the development of novel agents using the ‘Trojan horse’ approach have been reviewed.

Examples

Fruit flies infected by GFP-producing bacteria. Red-eyed flies lacking antimicrobial peptide genes are susceptible to infection, while white-eyed flies have a wild-type immune response.

Antimicrobial peptides are produced by species across the tree of life, including:

• bacteria (e.g. bacteriocin, and many others)
• fungi (e.g. peptaibols, plectasin, and many others)
• cnidaria (e.g. hydramacin, aurelin)
• many from insects and arthropods (e.g. cecropin, attacin, melittin, mastoparan, drosomycin, thioester-containing protein 1)
• amphibia, frogs (magainin, dermaseptin, aurein, and others)
• birds (e.g. avian defensins)
• and mammals (e.g. cathelicidins, alpha- and beta-defensins, regIII peptides)

Research has increased in recent years to develop artificially-engineered mimics of antimicrobial peptides such as SNAPPs, in part due to the prohibitive cost of producing naturally-derived AMPs. An example of this is the facially cationic peptide C18G, which was designed from the C-terminal domain of human platelet factor IV. Currently, the most widely used antimicrobial peptide is nisin; being the only FDA approved antimicrobial peptide, it is commonly used as an artificial preservative.

Bioinformatics

Several bioinformatic databases exist to catalogue antimicrobial peptides. The Antimicrobial Peptide Database (APD) is the original and model database for antimicrobial peptides (https://aps.unmc.edu). Based on the APD, other databases have also been built, including ADAM (A Database of Anti-Microbial peptides), BioPD (Biologically active Peptide Database), CAMP (Collection of sequences and structures of antimicrobial peptides), DBAASP (Database of Antimicrobial Activity and Structure of Peptides), DRAMP (Data Repository of Antimicrobial Peptides)Welcome To Dramp Database, and LAMP (Linking AMPs).

The Antimicrobial peptide databases may be divided into two categories on the basis of the source of peptides it contains, as specific databases and general databases. These databases have various tools for antimicrobial peptides analysis and prediction. For example, the APD has a widely used calculation interface. It also provides links to many other tools. CAMP contains AMP prediction, feature calculator, BLAST search, ClustalW, VAST, PRATT, Helical wheel etc. In addition, ADAM allows users to search or browse through AMP sequence-structure relationships. Antimicrobial peptides often encompass a wide range of categories such as antifungal, antibacterial, and antituberculosis peptides.

dbAMP: Provides an online platform for exploring antimicrobial peptides with functional activities and physicochemical properties on transcriptome and proteome data. dbAMP is an online resource that addresses various topics such as annotations of antimicrobial peptides (AMPs) including sequence information, antimicrobial activities, post-translational modifications (PTMs), structural visualization, antimicrobial potency, target species with minimum inhibitory concentration (MIC), physicochemical properties, or AMP–protein interactions.

Tools such as PeptideRanker, PeptideLocator, and AntiMPmod allow for the prediction of antimicrobial peptides while others have been developed to predict antifungal and anti-Tuberculosis activities.

Disinfection by-product

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Disinfection_by-product

Disinfection by-products (DBPs) are organic and inorganic compounds resulting from chemical reactions between organic and inorganic substances such as contaminates and chemical treatment disinfection agents, respectively, in water during water disinfection processes.

Chlorination disinfection byproducts

Chlorinated disinfection agents such as chlorine and monochloramine are strong oxidizing agents introduced into water in order to destroy pathogenic microbes, to oxidize taste/odor-forming compounds, and to form a disinfectant residual so water can reach the consumer tap safe from microbial contamination. These disinfectants may react with naturally present fulvic and humic acids, amino acids, and other natural organic matter, as well as iodide and bromide ions, to produce a range of DBPs such as the trihalomethanes (THMs), haloacetic acids (HAAs), bromate, and chlorite (which are regulated in the US), and so-called "emerging" DBPs such as halonitromethanes, haloacetonitriles, haloamides, halofuranones, iodo-acids such as iodoacetic acid, iodo-THMs (iodotrihalomethanes), nitrosamines, and others.

Chloramine has become a popular disinfectant in the US, and it has been found to produce N-nitrosodimethylamine (NDMA), which is a possible human carcinogen, as well as highly genotoxic iodinated DBPs, such as iodoacetic acid, when iodide is present in source waters.

Residual chlorine and other disinfectants may also react further within the distribution network – both by further reactions with dissolved natural organic matter and with biofilms present in the pipes. In addition to being highly influenced by the types of organic and inorganic matter in the source water, the different species and concentrations of DBPs vary according to the type of disinfectant used, the dose of disinfectant, the concentration of natural organic matter and bromide/iodide, the time since dosing (i.e. water age), temperature, and pH of the water.

Swimming pools using chlorine have been found to contain trihalomethanes, although generally they are below current EU standard for drinking water (100 micrograms per litre). Concentrations of trihalomethanes (mainly chloroform) of up to 0.43 ppm have been measured. In addition, trichloramine has been detected in the air above swimming pools, and it is suspected in the increased asthma observed in elite swimmers. Trichloramine is formed by the reaction of urea (from urine and sweat) with chlorine and gives the indoor swimming pool its distinctive odor.

Byproducts from non-chlorinated disinfectants

Several powerful oxidizing agents are used in disinfecting and treating drinking water, and many of these also cause the formation of DBPs. Ozone, for example, produces ketones, carboxylic acids, and aldehydes, including formaldehyde. Bromide in source waters can be converted by ozone into bromate, a potent carcinogen that is regulated in the United States, as well as other brominated DBPs.

As regulations are tightened on established DBPs such as THMs and HAAs, drinking water treatment plants may switch to alternative disinfection methods. This change will alter the distribution of classes of DBPs.

Occurrence

DBPs are present in most drinking water supplies that have been subject to chlorination, chloramination, ozonation, or treatment with chlorine dioxide. Many hundreds of DBPs exist in treated drinking water and at least 600 have been identified. The low levels of many of these DBPs, coupled with the analytical costs in testing water samples for them, means that in practice only a handful of DBPs are actually monitored. Increasingly it is recognized that the genotoxicities and cytotoxicities of many of the DBPs not subject to regulatory monitoring, (particularly iodinated, nitrogenous DBPs) are comparatively much higher than those DBPs commonly monitored in the developed world (THMs and HAAs).

In 2021, a new group of DBPs known as halogenated pyridinols was discovered, containing at least 8 previously unknown heterocyclic nitrogenous DBPs. They were found to require low pH treatments of 3.0 to be removed effectively. When their developmental and acute toxicity was tested on zebrafish embryos, it found to be slightly lower than those of halogenated benzoquinones, but dozens of times higher than of commonly known DBPs such as tribromomethane and iodoacetic acid. 

Health effects

Epidemiological studies have looked at the associations between exposure to DBPs in drinking water with cancers, adverse birth outcomes and birth defects. Meta-analyses and pooled analyses of these studies have demonstrated consistent associations for bladder cancer and for babies being born small for gestational age, but not for congenital anomalies (birth defects). Early-term miscarriages have also been reported in some studies. The exact putative agent remains unknown, however, in the epidemiological studies since the number of DBPs in a water sample are high and exposure surrogates such as monitoring data of a specific by-product (often total trihalomethanes) are used in lieu of more detailed exposure assessment. The World Health Organization has stated that "the risk of death from pathogens is at least 100 to 1000 times greater than the risk of cancer from disinfection by-products (DBPs)" {and} the "risk of illness from pathogens is at least 10 000 to 1 million times greater than the risk of cancer from DBPs".

Regulation and monitoring

The United States Environmental Protection Agency has set Maximum Contaminant Levels (MCLs) for bromate, chlorite, haloacetic acids and total trihalomethanes (TTHMs). In Europe, the level of TTHMs has been set at 100 micrograms per litre, and the level for bromate to 10 micrograms per litre, under the Drinking Water Directive. No guideline values have been set for HAAs in Europe. The World Health Organization has established guidelines for several DBPs, including bromate, bromodichloromethane, chlorate, chlorite, chloroacetic acid, chloroform, cyanogen chloride, dibromoacetonitrile, dibromochloromethane, dichloroacetic acid, dichloroacetonitrile, NDMA, and trichloroacetic acid.

Health risk assessment

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Health_risk_assessment

A health risk assessment (also referred to as a health risk appraisal and health & well-being assessment) is a questionnaire about a person's medical history, demographic characteristics and lifestyle. It is one of the most widely used screening tools in the field of health promotion and is often the first step in multi-component health promotion programs.

Definition

A health risk assessment (HRA) is a health questionnaire, used to provide individuals with an evaluation of their health risks and quality of life. Commonly a HRA incorporates three key elements – an extended questionnaire, a risk calculation or score, and some form of feedback, i.e. face-to-face with a health advisor or an automatic online report.

The Centers for Disease Control and Prevention define a HRA as: "a systematic approach to collecting information from individuals that identifies risk factors, provides individualised feedback, and links the person with at least one intervention to promote health, sustain function and/or prevent disease".

There is a range of different HRAs available for adults and children. Some target specific populations. For example, in the US, Medicare HRAs ask seniors about their ability to perform daily activities. Medicaid assessments ask questions about health-care access, availability of food, and living conditions. Most HRAs capture information relating to:

• Demographic characteristics – age, sex
• Lifestyle – exercise, smoking, alcohol intake, diet
• Personal and family medical history (in the US, due to the current interpretation of the Genetic Information Nondiscrimination Act, questions regarding family medical history are not permitted if there is any incentive attached to taking a HRA)
• Physiological data – weight, height, blood pressure, cholesterol
• Attitudes and willingness to change behaviour in order to improve health

The main objectives of a HRA are to:

• Assess health status
• Estimate the level of health risk
• Inform and provide feedback to participants to motivate behaviour change to reduce health risks

In the US, HRAs used as part of the Medicare Annual Wellness Visit help identify issues important to a senior's health and well-being. HRAs used as part of Medicaid enrollment help identify individuals with health problems that need immediate attention. The Community Preventive Services Task Force (CPSTF) recommends the use of HRAs in workplace settings when used in combination with health education, having found there is strong or satisfactory evidence that they help improve the following behaviors among employees:

• Tobacco
• Consuming too much alcohol
• Seat belts
• Fat consumption
• Blood pressure
• Absenteeism
• Healthcare services use
• Summary health risk estimates

History

The original concept of the HRA can be traced back to the decision by the assistant Surgeon General of the United States to conduct a study to determine the probable 10-year lifespan of individuals based on lifestyles and predisposed conditions. The project, led by Lewis C. Robbins, MD, of the Public Health Service, was the Framingham study. The study was based on in-depth longitudinal studies of 5,000 families in Framingham, Massachusetts, that continues to this day under funding from the National Institutes of Health.

Dr. Robbins left the Public Health Service and joined Methodist Hospital in Indianapolis where, working with Jack Hall, M.D., he developed the first set of health hazard tables. This culminated in the publication of How to Practice Prospective Medicine in 1970 – a guide for practising physicians, which outlined the health risk assessment questionnaire, risk computations and patient feedback strategies. During the 1960s, some researchers in California formed the Human Population Laboratory (HPL) to investigate factors contributing to quality of life. Inspired by a research article reporting on the HPL's Alameda County Study on the best lifestyle practices for good health, Don R. Hall, DrPH, developed a Health Age Assessment algorithm on a calculator while a masters student at Loma Linda University in 1972. In 1977, Hall coded his longevity calculations on a TRS-80, creating the first computerized health risk assessment. Within a year, he had programmed 12 health assessments on single topics such as nutrition, fitness, weight, and stress. In 1979, when personal desktop computers became readily available, he packaged all 12 assessments together on a floppy disk and marketed it as a comprehensive health risk assessment.

It was not until 1980, when the Centers for Disease Control and Prevention released a publicly available version, that the HRA became widely used, particularly in workplace settings. Health and Welfare Canada reviewed How to Practice Prospective Medicine and created a mainframe version of the book. The Centers for Disease Control became aware of this product and adapted it to the newly available personal computer. When Prudential Life Insurance also took an interest and asked to fund an update of the program, the CDC, which could not accept private project funding at the time, transferred ownership to the Carter Center at Emory University where it was updated from 1986 to 1987. The transfer and subsequent program were managed by Dr. Ed Hutchins, who had worked on the HRA in positions at the University of Pennsylvania and Charlotte-Mecklenburg Hospital. At Charlotte Mecklenburg, he secured a contract with the World Health Organization to create a mainframe product that could be used on an international basis. The HRA was managed as a not-for-profit product. Copies were distributed to every state health department, and liaisons were assigned to each to work with their staffs to evaluate related data. Over 2,000 copies of the software were distributed to users who requested it, and approximately 70 copies of the code were provided to for-profit companies that were interested in developing proprietary products. This proliferation coincided with the rapid growth in interest in corporate health promotion programs as awareness developed on health risks and for-profit vendors monetized the programs.

The Carter Center's interest shifted to Africa and Dr. Hutchins founded the Healthier People Network (HPN) in 1991 to continue the work. HPN raised funds to support the HRA, but additional funding was not forthcoming from government sources. As a result, the Carter Center and HPN could not underwrite basic supporting activities such as annual conferences and, over time, the State-based liaison network and associated intellectual capital atrophied as programs lost funding and liaisons moved on.

The use of HRAs and corporate wellness programs has been most prevalent in the United States, with comparatively slower growth elsewhere. However, there has been recent strong growth in corporate wellness outside the US, particularly in Europe and Asia.

Usage

Once an individual completes a HRA, they usually receive a report, detailing their health rating or score, often broken down into specific sub scores and areas such as stress, nutrition and fitness. The report can also provide recommendations on how individuals can reduce their health risks by changing their lifestyle.

In addition to individual feedback, HRAs are also used to provide aggregated data reporting for employers and organizations. These reports include demographic data of participants, highlight health risk areas and often include cost projections and savings in terms of increased healthcare, absence and productivity. Organization-level reports can then be used to provide a first step by which organizations can target and monitor appropriate health interventions within their workforce.

HRA delivery

The delivery of HRAs has changed over the years in conjunction with advances in technology. Initially distributed as paper-based, self-scoring questionnaires through on-site workplace health promotion sessions, HRAs are now most commonly implemented online. Other delivery methods include telephone, mail and face-to-face.

The advantages of online HRAs include:

• Tailoring – online HRAs can adapt content based on an individual's answers to the HRA questionnaire to provide a personalised, relevant and interactive user experience.
• Improved data management
• Reduced administrative costs
• Instant feedback

Efficacy

Extensive research has shown that HRAs can be used effectively to:

• Identify health risk factors
• Predict health-related costs
• Measure absenteeism and presenteeism
• Evaluate the efficacy and return on investment of health promotion strategies

There is also recent evidence to suggest that taking a HRA alone can have a positive effect on health behavior change and health status. However, it is generally accepted that HRAs are most effective at promoting behavior change when they form part of an integrated, multi-component health promotion program. Applied in this way, the HRA is used primarily as a tool to identify health risks within a population and then target health interventions and behavior change programs to address these areas.

Limitations

The limitations of a HRA are largely related to its usage and it is important to recognise that a HRA highlights health risks but does not diagnose disease and should not replace consultation with a medical or health practitioner.

Providers

There are reportedly over 50 different HRA providers in the market, offering a variety of versions and formats. Major vendors generally have National Committee for Quality Assurance (NCQA) Wellness and Health Promotion (WHP) Certification or Health Information Products (HIP) Certification.

Monochloramine

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Monochloramine 

 

Monochloramine

Names
Other names Chloramine Chloramide

Properties
Chemical formula	NH 2Cl
Molar mass	51.476 g mol−1
Appearance	Colorless gas
Melting point	−66 °C (−87 °F; 207 K)
Acidity (pKa)	14
Basicity (pKb)	15
Hazards
Occupational safety and health (OHS/OSH):
Main hazards	Corrosive acid
Ingestion hazards	Corrosive; nausea and vomiting
Inhalation hazards	Corrosive
Eye hazards	Irritation
Skin hazards	Irritation
GHS labelling:
Pictograms
Signal word	Danger
Hazard statements	H290, H314, H315, H319, H335, H372, H412
Precautionary statements	P234, P260, P261, P264, P270, P271, P273, P280, P301+P330+P331, P302+P352, P303+P361+P353, P304+P340, P305+P351+P338, P310, P312, P314, P321, P332+P313, P337+P313, P362, P363, P390, P403+P233, P404, P405, P501
NFPA 704 (fire diamond)	3 1 1 ACID
Lethal dose or concentration (LD, LC):
LD50 (median dose)	935 mg/kg (rat, oral)
Related compounds
Related compounds	Ammonia Dichloramine Nitrogen trichloride Fluoroamine

Monochloramine, often called chloramine, is the chemical compound with the formula NH₂Cl. Together with dichloramine (NHCl₂) and nitrogen trichloride (NCl₃), it is one of the three chloramines of ammonia. It is a colorless liquid at its melting point of −66 °C (−87 °F), but it is usually handled as a dilute aqueous solution, in which form it is sometimes used as a disinfectant. Chloramine is too unstable to have its boiling point measured.

Water treatment

See also: Chloramination

Chloramine is used as a disinfectant for water. It is less aggressive than chlorine and more stable against light than hypochlorites.

Drinking water disinfection

Chloramine is commonly used in low concentrations as a secondary disinfectant in municipal water distribution systems as an alternative to chlorination. This application is increasing. Chlorine (referred to in water treatment as free chlorine) is being displaced by chloramine—to be specific, monochloramine—which is much less reactive and does not dissipate as rapidly as free chlorine. Chloramine also has a much lower, but still active, tendency than free chlorine to convert organic materials into chlorocarbons such as chloroform and carbon tetrachloride. Such compounds have been identified as carcinogens and in 1979 the United States Environmental Protection Agency (EPA) began regulating their levels in US drinking water.

Some of the unregulated byproducts may possibly pose greater health risks than the regulated chemicals.

Due to its acidic nature, adding chloramine to the water supply may increase exposure to lead in drinking water, especially in areas with older housing; this exposure can result in increased lead levels in the bloodstream, which may pose a significant health risk. Fortunately, water treatment plants can add caustic chemicals at the plant which have the dual purpose of reducing the corrosivity of the water, and stabilizing the disinfectant.

Swimming pool disinfection

In swimming pools, chloramines are formed by the reaction of free chlorine with amine groups present in organic substances, mainly those biological in origin (e.g., urea in sweat and urine). Chloramines, compared to free chlorine, are both less effective as a sanitizer and, if not managed correctly, more irritating to the eyes of swimmers. Chloramines are responsible for the distinctive "chlorine" smell of swimming pools, which is often misattributed to elemental chlorine by the public. Some pool test kits designed for use by homeowners do not distinguish free chlorine and chloramines, which can be misleading and lead to non-optimal levels of chloramines in the pool water. There is also evidence that exposure to chloramine can contribute to respiratory problems, including asthma, among swimmers. Respiratory problems related to chloramine exposure are common and prevalent among competitive swimmers.

Though chloramine's distinctive smell has been described by some as pleasant and even nostalgic, its formation in pool water as a result of bodily fluids being exposed to chlorine can be minimised by encouraging showering and other hygiene methods prior to entering the pool, as well as refraining from swimming while suffering from digestive illnesses and taking breaks to use the bathroom.

Safety

US EPA drinking water quality standards limit chloramine concentration for public water systems to 4 parts per million (ppm) based on a running annual average of all samples in the distribution system. In order to meet EPA-regulated limits on halogenated disinfection by-products, many utilities are switching from chlorination to chloramination. While chloramination produces fewer regulated total halogenated disinfection by-products, it can produce greater concentrations of unregulated iodinated disinfection byproducts and N-nitrosodimethylamine. Both iodinated disinfection by-products and N-nitrosodimethylamine have been shown to be genotoxic, causing damage to the genetic information within a cell resulting in mutations which may lead to cancer.

Lead poisoning incidents

In the year 2000, Washington, DC, switched from chlorine to monochloramine, causing lead to leach from unreplaced pipes. The number of babies with elevated blood lead levels rose about tenfold, and by one estimate fetal deaths rose between 32% and 63%.

Trenton, Missouri made the same switch, causing about one quarter of tested households to exceed EPA drinking water lead limits in the period from 2017 to 2019. 20 children tested positive for lead poisoning in 2016 alone. In 2023, Virginia Tech Professor Marc Edwards said lead spikes occur in several water utility system switchovers per year, due to lack of sufficient training and lack of removal of lead pipes. Lack of utility awareness that lead pipes are still in use is also part of the problem; the EPA has required all water utilities in the United States to prepare a complete lead pipe inventory by October 16, 2024.

Synthesis and chemical reactions

Chloramine is a highly unstable compound in concentrated form. Pure chloramine decomposes violently above −40 °C (−40 °F). Gaseous chloramine at low pressures and low concentrations of chloramine in aqueous solution are thermally slightly more stable. Chloramine is readily soluble in water and ether, but less soluble in chloroform and carbon tetrachloride.

Production

In dilute aqueous solution, chloramine is prepared by the reaction of ammonia with sodium hypochlorite:

NH₃ + NaOCl → NH₂Cl + NaOH

This reaction is also the first step of the Olin Raschig process for hydrazine synthesis. The reaction has to be carried out in a slightly alkaline medium (pH 8.5–11). The acting chlorinating agent in this reaction is hypochlorous acid (HOCl), which has to be generated by protonation of hypochlorite, and then reacts in a nucleophilic substitution of the hydroxyl against the amino group. The reaction occurs quickest at around pH 8. At higher pH values the concentration of hypochlorous acid is lower, at lower pH values ammonia is protonated to form ammonium ions (NH⁺
₄), which do not react further.

The chloramine solution can be concentrated by vacuum distillation and by passing the vapor through potassium carbonate which absorbs the water. Chloramine can be extracted with ether.

Gaseous chloramine can be obtained from the reaction of gaseous ammonia with chlorine gas (diluted with nitrogen gas):

2 NH₃ + Cl₂ ⇌ NH₂Cl + NH₄Cl

Pure chloramine can be prepared by passing fluoroamine through calcium chloride:

2 NH₂F + CaCl₂ → 2 NH₂Cl + CaF₂

Decomposition

The covalent N−Cl bonds of chloramines are readily hydrolyzed with release of hypochlorous acid:

RR′NCl + H₂O ⇌ RR′NH + HOCl

The quantitative hydrolysis constant (K value) is used to express the bactericidal power of chloramines, which depends on their generating hypochlorous acid in water. It is expressed by the equation below, and is generally in the range 10⁻⁴ to 10⁻¹⁰ (2.8×10⁻¹⁰ for monochloramine):

${\displaystyle K=\frac{c_{{\text{RR}}^{\prime }\text{NH}}\cdot c_{\text{HOCl}}}{c_{{\text{RR}}^{\prime }\text{NCl}}}}$

In aqueous solution, chloramine slowly decomposes to dinitrogen and ammonium chloride in a neutral or mildly alkaline (pH ≤ 11) medium:

3 NH₂Cl → N₂ + NH₄Cl + 2 HCl

However, only a few percent of a 0.1 M chloramine solution in water decomposes according to the formula in several weeks. At pH values above 11, the following reaction with hydroxide ions slowly occurs:

3 NH₂Cl + 3 OH⁻ → NH₃ + N₂ + 3 Cl⁻ + 3 H₂O

In an acidic medium at pH values of around 4, chloramine disproportionates to form dichloramine, which in turn disproportionates again at pH values below 3 to form nitrogen trichloride:

2 NH₂Cl + H⁺ ⇌ NHCl₂ + NH⁺
₄

3 NHCl₂ + H⁺ ⇌ 2 NCl₃ + NH⁺
₄

At low pH values, nitrogen trichloride dominates and at pH 3–5 dichloramine dominates. These equilibria are disturbed by the irreversible decomposition of both compounds:

NHCl₂ + NCl₃ + 2 H₂O → N₂ + 3 HCl + 2 HOCl

Reactions

In water, chloramine is pH-neutral. It is an oxidizing agent (acidic solution: E° = +1.48 V, in basic solution E° = +0.81 V):

NH₂Cl + 2 H⁺ + 2 e⁻ → NH⁺
₄ + Cl⁻

Reactions of chloramine include radical, nucleophilic, and electrophilic substitution of chlorine, electrophilic substitution of hydrogen, and oxidative additions.

Chloramine can, like hypochlorous acid, donate positively charged chlorine in reactions with nucleophiles (Nu⁻):

Nu⁻ + NH₃Cl⁺ → NuCl + NH₃

Examples of chlorination reactions include transformations to dichloramine and nitrogen trichloride in acidic medium, as described in the decomposition section.

Chloramine may also aminate nucleophiles (electrophilic amination):

Nu⁻ + NH₂Cl → NuNH₂ + Cl⁻

The amination of ammonia with chloramine to form hydrazine is an example of this mechanism seen in the Olin Raschig process:

NH₂Cl + NH₃ + NaOH → N₂H₄ + NaCl + H₂O

Chloramine electrophilically aminates itself in neutral and alkaline media to start its decomposition:

2 NH₂Cl → N₂H₃Cl + HCl

The chlorohydrazine (N₂H₃Cl) formed during self-decomposition is unstable and decomposes itself, which leads to the net decomposition reaction:

3 NH₂Cl → N₂ + NH₄Cl + 2 HCl

Monochloramine oxidizes sulfhydryls and disulfides in the same manner as hypochlorous acid, but only possesses 0.4% of the biocidal effect of HClO.

Nitrogen trichloride

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Nitrogen_trichloride 

 

Nitrogen trichloride

Nitrogen, N   Chlorine, Cl
Names
Other names Trichloramine Agene Nitrogen(III) chloride Trichloroazane Trichlorine nitride

Properties
Chemical formula	NCl3
Molar mass	120.36 g·mol−1
Appearance	yellow oily liquid
Odor	chlorine-like
Density	1.653 g/mL
Melting point	−40 °C (−40 °F; 233 K)
Boiling point	71 °C (160 °F; 344 K)
Solubility in water	immiscible slowly decomposes
Solubility	soluble in benzene, chloroform, CCl4, CS2, PCl3
Structure
Crystal structure	orthorhombic (below −40 °C)
Molecular shape	trigonal pyramidal
Dipole moment	0.6 D
Thermochemistry
Std enthalpy of formation (ΔfH⦵298)	232 kJ/mol
Hazards
NFPA 704 (fire diamond)	2 0 4 OX
Autoignition temperature	93 °C (199 °F; 366 K)
Related compounds
Other anions	Nitrogen trifluoride Nitrogen tribromide Nitrogen triiodide
Other cations	Phosphorus trichloride Arsenic trichloride
Related chloramines	Monochloramine Dichloramine
Related compounds	Nitrosyl chloride

Nitrogen trichloride, also known as trichloramine, is the chemical compound with the formula NCl₃. This yellow, oily, and explosive liquid is most commonly encountered as a product of chemical reactions between ammonia-derivatives and chlorine (for example, in swimming pools). Alongside monochloramine and dichloramine, trichloramine is responsible for the distinctive 'chlorine smell' associated with swimming pools, where the compound is readily formed as a product from hypochlorous acid reacting with ammonia and other nitrogenous substances in the water, such as urea from urine.

Preparation and structure

The compound is prepared by treatment of ammonium salts, such as sal ammoniac with a chlorine source.

Intermediates in this conversion include monochloramine and dichloramine, NH₂Cl and NHCl₂, respectively.

Like ammonia, NCl₃ is a pyramidal molecule. The N-Cl distances are 1.76 Å, and the Cl-N-Cl angles are 107°.

Reactions and uses

The chemistry of NCl₃ has been well explored. It is moderately polar with a dipole moment of 0.6 D. The nitrogen center is basic but much less so than ammonia. It is hydrolyzed by hot water to release ammonia and hypochlorous acid.

${\displaystyle {\text{NCl}}_3^{}+3{\text{H}}_2^{}\text{O}⟶{\text{NH}}_3^{}+3\text{HOCl}}$

${\displaystyle {\text{NCl}}_3^{}}$ explodes to give ${\displaystyle {\text{N}}_2^{}}$ and chlorine gas.

${\displaystyle 2{\text{NCl}}_3^{}⟶{\text{N}}_2^{}+3{\text{Cl}}_2^{}}$

This reaction is inhibited for dilute gases.

Nitrogen trichloride can form in small amounts when public water supplies are disinfected with monochloramine, and in swimming pools by disinfecting chlorine reacting with urea in urine and sweat from bathers.

Nitrogen trichloride, trademarked as Agene, was at one time used to bleach flour, but this practice was banned in the United States in 1949 due to safety concerns.

Safety

Nitrogen trichloride can irritate mucous membranes—it is a lachrymatory agent, but has never been used as such. The pure substance (rarely encountered) is a dangerous explosive, being sensitive to light, heat, even moderate shock, and organic compounds. Pierre Louis Dulong first prepared it in 1812, and lost several fingers and an eye in two explosions. In 1813, an NCl₃ explosion blinded Sir Humphry Davy temporarily, inducing him to hire Michael Faraday as a co-worker. They were both injured in another NCl₃ explosion shortly thereafter.

Risk factor

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Risk_factor

In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection.

Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often used as a synonym. The main difference lies in the realm of practice: medicine (clinical practice) versus public health. As an example from clinical practice, low ingestion of dietary sources of vitamin C is a known risk factor for developing scurvy. Specific to public health policy, a determinant is a health risk that is general, abstract, related to inequalities, and difficult for an individual to control. For example, poverty is known to be a determinant of an individual's standard of health.

Risk factors may be used to identify high-risk people.

Correlation vs causation

Risk factors or determinants are correlational and not necessarily causal, because correlation does not prove causation. For example, being young cannot be said to cause measles, but young people have a higher rate of measles because they are less likely to have developed immunity during a previous epidemic. Statistical methods are frequently used to assess the strength of an association and to provide causal evidence, for example in the study of the link between smoking and lung cancer. Statistical analysis along with the biological sciences can establish that risk factors are causal. Some prefer the term risk factor to mean causal determinants of increased rates of disease, and for unproven links to be called possible risks, associations, etc.

When done thoughtfully and based on research, identification of risk factors can be a strategy for medical screening.

Terms of description

Mainly taken from risk factors for breast cancer, risk factors can be described in terms of, for example:

• Relative risk, such as "A woman is more than 100 times more likely to develop breast cancer in her 60s than in her 20s."
• Fraction of incidences occurring in the group having the property of or being exposed to the risk factor, such as "99% of breast cancer cases are diagnosed in women."
• Increase in incidence in the exposed group, such as "each daily alcoholic beverage increases the incidence of breast cancer by 11 cases per 1000 women."
• Hazard ratio, such as "an increase in both total and invasive breast cancers in women randomized to receive estrogen and progestin for an average of 5 years, with a hazard ratio of 1.24 compared to controls."

Example

At a wedding, 74 people ate the chicken and 22 of them were ill, while of the 35 people who had the fish or vegetarian meal only 2 were ill. Did the chicken make the people ill?

${\displaystyle Risk=\frac{\text{number of persons experiencing event (food poisoning)}}{\text{number of persons exposed to risk factor (food)}}}$

So the chicken eaters' risk = 22/74 = 0.297
And non-chicken eaters' risk = 2/35 = 0.057.

Those who ate the chicken had a risk over five times as high as those who did not, that is, a relative risk of more than five. This suggests that eating chicken was the cause of the illness, but this is not proof.

This example of a risk factor is described in terms of the relative risk it confers, which is evaluated by comparing the risk of those exposed to the potential risk factor to those not exposed.

General determinants

The probability of an outcome usually depends on an interplay between multiple associated variables. When performing epidemiological studies to evaluate one or more determinants for a specific outcome, the other determinants may act as confounding factors, and need to be controlled for, e.g. by stratification. The potentially confounding determinants varies with what outcome is studied, but the following general confounders are common to most epidemiological associations, and are the determinants most commonly controlled for in epidemiological studies:

• Age (0 to 1.5 years for infants, 1.5 to 6 years for young children, etc.)
• Sex or gender (Male or female)
• Ethnicity (Based on race)

Other less commonly adjusted for possible confounders include:

• Social status/income
• Geographic location
• Genetic predisposition
• Gender identity
• Occupation
• Overwork
• Sexual orientation
• Level of chronic stress
• Diet
• Level of physical exercise
• Alcohol consumption and tobacco smoking
• Other social determinants of health

Risk marker

A risk marker is a variable that is quantitatively associated with a disease or other outcome, but direct alteration of the risk marker does not necessarily alter the risk of the outcome. For example, driving-while-intoxicated (DWI) history is a risk marker for pilots as epidemiologic studies indicate that pilots with a DWI history are significantly more likely than their counterparts without a DWI history to be involved in aviation crashes.

History

The term "risk factor" was coined by former Framingham Heart Study director, William B. Kannel in a 1961 article in Annals of Internal Medicine.