Editing Synergy (section)

==Biological sciences==
Synergy of various kinds has been advanced by [[Peter Corning]] as a causal agency that can explain the progressive evolution of complexity in living systems over the course of time. According to the Synergism Hypothesis, synergistic effects have been the drivers of cooperative relationships of all kinds and at all levels in living systems. The thesis, in a nutshell, is that synergistic effects have often provided functional advantages (economic benefits) in relation to survival and reproduction that have been favored by natural selection.  The cooperating parts, elements, or individuals become, in effect, functional "units" of selection in evolutionary change.<ref>{{cite book | vauthors = Corning PA |title=The synergism hypothesis : a theory of progressive evolution |date=1983 |publisher=McGraw-Hill |location=New York |isbn=978-0-07-013166-8}}</ref><ref>{{cite book | vauthors = Corning PA |title=Holistic Darwinism : synergy, cybernetics, and the bioeconomics of evolution |date=2005 |publisher=University of Chicago Press |location=Chicago |isbn=978-0-226-11613-6}}</ref><ref>{{cite journal | vauthors = Corning PA | title = Synergy and self-organization in the evolution of complex systems. | journal = Systems Research | date = 1995 | volume = 12 | issue = 2 | pages = 89–121 | doi = 10.1002/sres.3850120204 | url = http://www.complexsystems.org/publications/pdf/synselforg.pdf | archive-url = https://web.archive.org/web/20110720103635/http://www.complexsystems.org/publications/pdf/synselforg.pdf | archive-date=2011-07-20 }}</ref> Similarly, environmental systems may react in a non-linear way to perturbations, such as climate change, so that the outcome may be greater than the sum of the individual component alterations. Synergistic responses are a complicating factor in environmental modeling.<ref name="pmid17841254">{{cite journal | vauthors = Myers N | title = Environmental unknowns | journal = Science | location = New York, N.Y. | volume = 269 | issue = 5222 | pages = 358–60 | date = July 1995 | pmid = 17841254 | doi = 10.1126/science.269.5222.358 | bibcode = 1995Sci...269..358M | s2cid = 45407924 }}</ref>

===Pest synergy===
Pest synergy would occur in a [[biology|biological]] [[Host (biology)|host]] [[organism]] population, where, for example, the introduction of [[parasite]] A may cause 10% fatalities, and parasite B may also cause 10% loss. When both parasites are present, the losses would normally be expected to total less than 20%, yet, in some cases, losses are significantly greater. In such cases, it is said that the parasites in combination have a synergistic effect.

=== Drug synergy ===
{{also|Codrug#Common codrugs|Combination drug#Common combination drugs}}

Mechanisms that may be involved in the development of synergistic effects include:
*Effect on the same cellular system (e.g. two different [[antibiotics]] like a [[penicillin]] and an [[aminoglycoside]]; penicillins damage the cell wall of gram-positive [[bacteria]] and improve the penetration of aminoglycosides).<ref name = "Tripathi_2013">{{cite book | vauthors = Tripathi KD |title=Essentials of medical pharmacology |date=2013 |location=New Delhi | publisher = JP Medical Ltd |isbn=9789350259375 |edition=Seventh }}</ref>{{rp|698}}
*[[Bioavailability]] (e.g. [[ayahuasca]] (or [[pharmahuasca]]) consists of [[N,N-Dimethyltryptamine|DMT]] combined with [[Monoamine oxidase inhibitor|MAOIs]] that interfere with the action of the MAO enzyme and stop the breakdown of chemical compounds such as DMT).
*Reduced risk for [[substance abuse]] (e.g. [[lisdexamfetamine]], which is a combination of the [[amino acid]] [[Lysine|<small>L</small>-lysine]], [[covalently bonded|attached to]] [[dextroamphetamine]], may have a lower liability for abuse as a recreational drug)
*Increased potency (e.g. as with other [[Nonsteroidal anti-inflammatory drug|NSAIDs]], [[Compound analgesic|combinations]] of aspirin and [[caffeine]] provide slightly greater pain relief than aspirin alone.<ref name=pmid22419343>{{cite journal | vauthors = Derry CJ, Derry S, Moore RA | title = Caffeine as an analgesic adjuvant for acute pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 3 | pages = CD009281 | date = March 2012 | pmid = 22419343 | doi = 10.1002/14651858.CD009281.pub2 | s2cid = 205199173 | veditors = Derry S }}</ref>).
*Prevention or delay of degradation in the body (e.g. the antibiotic [[Ciprofloxacin]] inhibits the metabolism of [[Theophylline]]).<ref name = "Tripathi_2013" />{{rp|931}}
*Slowdown of excretion (e.g. [[Probenecid]] delays the [[renal]] excretion of Penicillin and thus prolongs its effect).<ref name = "Tripathi_2013" />{{rp|931}}
*Anticounteractive action: for example, the effect of [[oxaliplatin]] and [[irinotecan]]. Oxaliplatin [[wikt:intercalation|intercalates]] DNA, thereby preventing the cell from replicating DNA. Irinotecan inhibits [[topoisomerase 1]], consequently the cytostatic effect is increased.<ref name="Jia_2009">{{cite journal | vauthors = Jia J, Zhu F, Ma X, Cao Z, Cao ZW, Li Y, Li YX, Chen YZ | title = Mechanisms of drug combinations: interaction and network perspectives | journal = Nature Reviews. Drug Discovery | volume = 8 | issue = 2 | pages = 111–28 | date = February 2009 | pmid = 19180105 | doi = 10.1038/nrd2683 | s2cid = 54466254 }}</ref>
*Effect on the same receptor but different sites (e.g. the coadministration of benzodiazepines and barbiturates, both act by enhancing the action of GABA on GABA<sub>A</sub> receptors, but benzodiazepines increase the frequency of channel opening, whilst barbiturates increase the channel closing time, making these two drugs dramatically enhance GABAergic neurotransmission).{{citation needed|date=May 2018}}
* In addition to the chemical nature of the drug itself, the topology of the chemical reaction network that connect the two targets determines the type of drug-drug interaction.<ref>Mehrad Babaei et al., Biochemical reaction network topology defines dose-dependent Drug–Drug interactions. Comput Biol Med 155:106584 (2023)  doi: 10.1016/j.compbiomed.2023.106584</ref> 

More mechanisms are described in an exhaustive 2009 review.<ref name="Jia_2009"/>

===Toxicological synergy===
Toxicological synergy is of concern to the public and regulatory agencies because chemicals individually considered safe might pose unacceptable health or ecological risk in combination. Articles in scientific and lay journals include many definitions of chemical or toxicological synergy, often vague or in conflict with each other. Because toxic interactions are defined relative to the expectation under "no interaction", a determination of synergy (or antagonism) depends on what is meant by "no interaction".<ref name="pmid12013546">{{cite journal | vauthors = Hertzberg RC, MacDonell MM | title = Synergy and other ineffective mixture risk definitions | journal = The Science of the Total Environment | volume = 288 | issue = 1–2 | pages = 31–42 | date = April 2002 | pmid = 12013546 | doi = 10.1016/s0048-9697(01)01113-5  | bibcode = 2002ScTEn.288...31H }}</ref> The [[United States Environmental Protection Agency]] has one of the more detailed and precise definitions of toxic interaction, designed to facilitate risk assessment.<ref name="EPAMixRisk">{{cite web | vauthors = Choudhury H, Hertzberg R, Rice G, Cogliano J, Mukerjee D, Teuschler L, Doyle E, Woo Y, Schoeny R | display-authors = 6 | collaboration = Risk Assessment Forum Technical Panel | url = http://ofmpub.epa.gov/eims/eimscomm.getfile?p_download_id=4486 | publisher = U.S. EPA | date = August 2000 | title = Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures. | work = Risk Assessment Forum | location = Washington, DC }}</ref> In their guidance documents, the no-interaction default assumption is dose addition, so synergy means a mixture response that exceeds that predicted from dose addition. The EPA emphasizes that synergy does not always make a mixture dangerous, nor does antagonism always make the mixture safe; each depends on the predicted risk under dose addition.

For example, a consequence of pesticide use is the risk of health effects. During the registration of [[pesticide]]s in the [[United States]] exhaustive tests are performed to discern health effects on humans at various exposure levels. A regulatory upper limit of presence in foods is then placed on this pesticide. As long as residues in the food stay below this regulatory level, health effects are deemed highly unlikely and the food is considered safe to consume.

However, in normal agricultural practice, it is rare to use only a single pesticide. During the production of a crop, several different materials may be used. Each of them has had determined a regulatory level at which they would be considered individually safe. In many cases, a commercial pesticide is itself a combination of several chemical agents, and thus the safe levels actually represent levels of the mixture. In contrast, a combination created by the end user, such as a farmer, has rarely been tested in that combination. The potential for synergy is then unknown or estimated from data on similar combinations.  This lack of information also applies to many of the chemical combinations to which humans are exposed, including residues in food, indoor air contaminants, and occupational exposures to chemicals. Some groups think that the rising rates of cancer, asthma, and other health problems may be caused by these combination exposures; others have alternative explanations. This question will likely be answered only after years of exposure by the population in general and research on chemical toxicity, usually performed on animals. Examples of pesticide synergists include [[Piperonyl butoxide]] and [[MGK 264]].<ref>{{cite web | url = http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html | archive-url = https://web.archive.org/web/20110202121751/http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html | archive-date = 2 February 2011 | title = Pyrethroids and Pyrethrins | date = August 2010 | publisher = U.S. Environmental Protection Agency }}</ref>