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We had a hunch that word choice in email subject lines have a strong effect on response rates. So, we tested 287 keywords across a sample of 2.2bn emails to see which work, and which don't.
Why? Because President Obama has done more for email marketing than any world leader in the history of mankind. How? By focusing on subject line testing, his digital team optimised their donation campaigns to generate hundreds of millions of dollars online.
Despite Obama's best efforts, most marketers still view email marketing as the Bluth Company's Banana Stand of Arrested Development fame: a more boring and less sexy marketing channel than pretty much anything else imaginable.
But – and never forget this – there's always money in the banana stand! There is great power in optimising subject lines.
In case you missed my presentations at MarketingWeekLive last week, you can find out more about our findings after the jump.
We tested a random sample of 95,000 global, English-language campaigns over the last 12 months (for a total of 2.2bn emails), and have isolated 287 popular 'trigger words'.
Then, split by sector, we looked at the correlation between the word's inclusion in the subject line and its variance above or below the average results for key email metrics (Open Rate, CTR, CTOR, and Unsubscribe).
To ensure outliers aren't confusing things, we've also looked at the first, second and third quartiles to give an indication of data spread, not just nominal long-run means.
Bear in mind, these relationships are correlated, but not necessarily causal. There are simply too many variables in an email campaign to pinpoint exact causation. But, where there's smoke, there's fire, and at the very least, this will give you many ideas for what to test.
And now some key findings:
People love free stuff
In related news, water is wet. Specific trigger words have a drastic effect on the response rates of offers. For example, 'Sale' delivers +23.2% opens, but 'Save' only +3.4%.
However, in terms of click throughs, they give +60.7% and -25.2% respectively. When you promote your offers, consider testing those trigger words – it could make or break your campaigns.
And, consider simple quick wins like 'Free Delivery' or even '% off' - in the right context these keywords can drive massive response uplifts. But, if you do nothing but hard sell and offer discounts all the time, your customers will become bored and tune out.
Mix up your offer emails in a series of value-adding campaigns.
Content marketing works when the content isn't crap
The problem with content marketing is the vast majority of content produced is crap. Too many people have outsourced it to agencies that don't know enough about their clients' markets, and focus on the wrong metrics. As a result, consumers have become anesthetised to content.
Take, for example, 'Report' (-23.7% opens, -54.8% CTR) and Webinar' (-16.6%, -70.7%.)
Conversely if the content is good, people will consume it. So 'News' (+34.8%, +47.7%), 'Bulletin' (+15.8%, +12.7%) and 'Video' (+18.5%, +64.8%) work well.
Simply put, if your content is crap, it won't work. If your content is good, you'll get great results. When doing content marketing, make sure you're in the latter group, not the former, or else you'll be what we affectionately call in the industry a "spamming %$*!$#".
More frequent emails are better than less frequent
Typical for an email guy to say, right? Full disclosure, when people send out more emails, ESPs make more money, this is true. But, if emails drive response and therefore generate revenue, then what's the problem?
But, don't take my word for it. We looked at newsletter frequency, and specifically the trigger words that indicate it. 'Monthly' brought -26.6% opens and -37.0% clicks. 'Weekly' brought +27.1% and +50.6% (not bad) and, amazingly, 'Daily' brought +27.8% and +100.3%. Simply put, more email drives more response.
And it's not just us saying this, check this out if you're sceptical.
Personalisation works, if your data is clean
Lots of people have played around with subject line personalisation, with varied results. We found the average opens and clicks decrease (-20.7% opens). But, the spread of the data is massive. The first quartile is -73.1%, but the third quartile is +30.8%. Why is this?
The main thing about personalisation is to ensure you don't deliver users a disjointed user experience. If the subject line is personalised, but the email content isn't, guess what? You may gain opens, but have done nothing to drive clicks. It leaves users with a negative experience.
Furthermore, if the subsequent online journey isn't equally personalised, once again you've left your users feeling like you've given them the old bait-n-switch.
Most importantly, if your database is old and potentially incorrect, you're in trouble. Eyeball your data first and pick recent, engaged data for testing personalised content.
There's always money in the banana stand
This report analysed a vast sample of subject lines. More than anything, it showed there is lots of short-run variance in every keyword sample. What matters is that you test things out to your lists, and never stay standing still. What works one week may not work the next, but if you aren't trying out new things then you're treading water and ultimately throwing away money.
Email still delivers the strongest revenue of any digital channel by a country mile (source). In all your tweeting, pinning, and facebooking, are you making sure you dedicate enough time to your email subject lines?
Remember – of Obama's 30 person digital team, 24 of them were focused on email.
They knew that there's always money in the banana stand.
To see the full list of keywords (287 common words were tested in addition to the ones above), you can download the report. (Registration required - Ed)
Comments (29)
High response rates for certain words are a result of the campaigns those words are used in; It is not those words causing high open rates.
I did a similar study a couple of years ago and was surprised when 'lager' came out as one of the top words.
Context is everything. The word 'lager' was being used in German-language notification emails saying that the goods had left the warehouse - with Lager being the word used for warehouse.
It is not the words which cause the responses; but instead it is just that there are certain words which naturally appear in high-engagement campaigns.
For proof of this look at the variance of the open rates, not just the average.
@Steve - great point. I agree that context is everything. However, you'll note that I'm strictly looking at long run correlations and there is indeed a large spread of data, a function of context. With that said, there are clearly some words that across the board perform less strongly than others. I suppose the main point, at the risk of being blunt, is to not be stupid. (And I bet "Free lager" works even better, right?) It's important to note that this is an English-language only sample, so that will control for multilingual variance.
Regardless, I fundamentally believe that subject lines provide context for the entire email - so psychological cues that add to action-taking in the email itself. It puts people in a frame of mind when they're viewing the email content itself - sort of like a prompt to consider undertaking action later on in the web journey.
@kudani - more than happy to discuss your idea and my methodology. Can you suggest a better alternative?
So the title "Alert: Daily Sale, Free Delivery To Ipads: Video" Would be the very best title choice then :-p Great post Parry, really insightful!
High response rate can be achieved relevancy,offer & incentive in subject line. And remove friction and anxiety from the subject lines. Also,these words would definitely help to get more open rate.
@Steve You bring up an interesting point but I can't say I completely agree with what you're saying. Context IS everything. Lager coming out on top means nothing for businesses that don't sell lager. Just like the fact that "News" is a stronger subject word than "Report" or "Newsletter" means nothing to someone that is not emailing about news.
When you provide context, you can't ignore data. As always, it's a great tool to catch general trends that the human eye would miss. High-engagement emails most likely have something in common in order to attract clicks and click throughs.
In our market it's tricky. What about the word "sex"? Will it cause way more spam complaints?
@Fred - yeah, I get asked this a lot. The thing is, spam filters are more intelligent than back in the day, it's not just about content. It's about way more than that - sender reputation, infrastructure, data quality, engagement, etc. So if your brand sends out good emails to quality data, you can get around some of the old rules.
Anyways, the word "sex" (with spaces around each side to control for things like "essex") provide the following:
Open: +27.4%
Click: +175.6%
Unsubs: -81.4%
Spam complaints: -22.5%
Mind you, this is only on a sample of 450k emails, so could be some variance issue in there.
@Shoplet - true dat. This report is strictly looking at correlations between keywords and response metrics, but they don't exist in a vacuum. In no way am I saying "Don't use the word report" - what I am saying is, if you use that word, make sure it's relevant to the list, used non-stupidly, and relates to the content of the email (and the rest of the web journey to boot!)
Hey Parry, great article.
Love that stat about 'Sale' delivering +23.2% opens and 'Save' only +3.4%. Looking forward to going over the full report.
Regarding the "no smoke without fire" comment... ice cream sales and murder rates spring to mind, positively correlated in the summertime. Trite example but helps to keep it in mind when considering correlations
Did you find that adding urgency to a subject line increased opens / clicks?
i.e. Last chance, limited time offer etc
@trudi - for sure. And also, did you know that umbrella sales cause it to rain in London? :) So yeah, these are correlations (try finding causality with so many disparate variables!) but at the same time, the whole purpose of this exercise is to get people to think about their subject lines!
@Phil - so some worked sometimes, and some didn't other times. Great answer, right? Urgency can work but play around with different urgency drivers in the subject lines to see which ones your lists respond to the best.
> 152 killer keywords for email subject lines
Surely we are more sophisticated marketers than to think there are any easy solutions - some 'magic' trick.
There are no 'killer' keywords.
As others have said above - context is everything.
Is this a first email to someone who is not a customer, or an email they get every week: an email once in a blue moon with an offer, or an email after they have become a customer. An email asking for feedback. An email linked to a Fecbook cmpaign..a TV campaign,, a viral campaign...
All that context really does matter.
And this is simplistic:
> Simply put, more email drives more response.
Please people, don't take that as an OK to email every day!
Unless you have a marketing strategy that supports that.
As I said; we misunderstood marketing, if we think it is about blindly following magic recipe rules.
@Deri - I'm not sure you've interpreted the blog and the report in the way it is intended. For years email has taken a back seat to other channels - and people split test things like subject lines much less than they should.
This report is intended to get people thinking about subject lines - not a definitive list of which keywords work and which don't. Simplistic, perhaps - but if it gets email marketing back on the agenda for digital marketers then that's the most important thing.
Hi Parry
You sure you can square that circle?
> 152 killer keywords for email subject lines
> not a definitive list of which keywords work and which don't
@Deri - the purpose of a subject line is to get people to read the email... much like the purpose of a blog heading. Funny that, it seems to work.
@Parry - I think you deserve credit on two fronts here...
Firstly, for an interesting, thought-provoking post. The fact that it was the latter is clearly shown by some of the above comments. Which brings me onto the 2nd thing you deserve credit for... your patience in responding to some of the comments where people may just have missed the tone of your post :)
And according to Obama's marketing team, their best performing subject line was 'Hey'. Yep, that was it, apparently it brought them in millions of dollars (see http://goo.gl/pypV2 ).
Now if only Obama had gone with 'Free lager & sex'... Mind, then he'd probably have become Prime Minister of Italy instead ;)
@Dennis cheers - appreciate the feedback. I'm partial to "Free viagra delivered by Britney Spears with a guaranteed Nigerian lottery win"
My first thought is that Free is a spam word and should be avoided at all costs. Some useful tips in the article, and stats are great for re-inforcing my messages to clients who still think newsletters are the best way of communicating. I agree that context is important, talking to targeted audiences in the right language is key, not just picking key words. Thanks for sharing!
Forgive me if I'm the contrarian here...
Dennis - the evidence we should take away from the Obama campaign is not:
> according to Obama's marketing team, their best performing subject line was 'Hey'
Because that 3-letter Subject has NO wide-spread usefulness: we canot learn from that word what to put in our own Subject lines!
It's simply what was proven to work, in the situation of the Obama campaign, at the time they were using it.
It probably wouldn't even work as well if Obama himself used it again, in today's situation!
What we CAN learn as marketers and act on to our benefit - is the Process that they used, to find their best Subject lines: that process is something we can all use and will work in all our individual markets and brand situations:
"We did extensive A-B testing not just on the subject lines and the ... The campaign would test multiple drafts and subject lines—often as many as 18 variations—before picking a winner to blast out to tens of millions of subscribers. "When we saw something that really moved the dial, we would adopt it," says Toby Fallsgraff, the campaign's e-mail director, who oversaw a staff of 20 writers."
What we can NOT take away is that the word 'Sale' is somehow generically better than 'Save' - even if Parry's data did say it has better click-through.
(and anyway, click-through is one step removed from opening rates and Subject lines really only directly impact the latter, not the former)
Re using 'free', you might be interested in Hubspot's testing of this http://goo.gl/MCwmV that showed that surprisingly, it didn't affect deliverability, although it didn't pull such a good response for them, either (though there could of course be other reasons for that).
Thanks for the comment, but please be assured that if it appeared that I was suggesting that we all adopt 'Hey' as the ideal subject line, it is only because my typing must have been affected by my tongue being firmly in my cheek...
However, if writing more seriously, yes, I agree with you and Obama's team completely (and would suggest that this is the real relevance of the success of 'Hey') in that the key is to test, as what works for one won't for another, or even necessarily for yourself the next time, either!
But, what both Obama's team's results, and Parry's statistical analysis do help us with is firstly to make us realise that sometimes small changes can make a significant difference (for example, we've previously got a 28% higher open rate with the same subject line just by changing its capitalisation away from Title Case). And secondly, they sometimes make us think of changes that maybe we wouldn't have otherwise - like using short, sharp subjects in a personalised context, or maybe how much difference substituting one word for another with a very similar meaning could make.
As for whether or not 'Sale' is somehow generically better than 'save', sure, it doesn't prove it categorically; however, personally, if I had to opt for one over the other in an email subject line tomorrow and couldn't split-test them both, I'm happy to err on the side of Parry's results from 2.2bn emails. And coincidentally (or not) Adestra's stats from 2012 would suggest that it's the best-performing 'discount term', too - see point #22 here http://goo.gl/Qe9Op
Finally (phew), our constant analysis of our own clients' sends shows a very firm and very real correlation not just between subject lines and opens, but with the resultant click-throughs, too. We can always up someone's open rate with a nice, juicy subject line, but if it isn't relevant to its content, the clicks will die.
You make a completely valid point, but I think you're in danger of going round in circles. It's something that's made clear in the article:
Context is extremely important.
What the author's done is present us with some intriguing, 'food for thought' results which encourage us, as marketers, to continually monitor, tweak and split test our subject lines.
That's the takeaway here.
Of course there's no one size fits all. Context is key, but we can still learn from this data. Take some of the ideas, tweak them for your niche and then test, test, test.
Far better an approximate answer to the right question, which is often vague, than an exact answer to the wrong question, which can always be made precise.' -Tukey
These are the right questions in this post.
@Chuck & @Tukey:
Wise words and succinctly put.
What is remarkable about this post is that a lot of business are doing this. They might get a lot of things by reading this post. I know I learned something. Thanks a lot! www.zipyourflyer.com
152 + 137 = 289 - but you state you have 287 keywords are you hiding 2 of the keywords?? ;)
Improve your subject lines – instantly
Alchemy Worx launch Touchstone - new Subject Line results predictor and optimisation tool. It will do away with the need to A/B split test. Sign up for the Beta trial now!
http://www.subjectlinegold.com - its free!


text:
World Youth Day Madrid's executive director, Yago de la Cierva, has been busily preparing for the Aug. 16-21 festival of Catholic faith.
As the chief organizer, de la Cierva explained, from Rome on June 28, how pilgrims could best prepare for WYD, the reasons for holding the event in Madrid, the Pope's decision to hear confessions, and how Spain's secularist government is handling the event.
How have the preparations gone for World Youth Day?
Everything is on schedule, and the preparations are going quite well, both because of the large number of volunteers working on this, but also because of the collaboration from public administration and civil society — sponsors, companies, individuals — and the fact that both the government, the mayor and the region are cooperating with a really great spirit of collaboration. So, this is very good.
Is this a surprise, given the secularist nature of the government?
I think this goes beyond a religious event, and the government is well aware of that. It means that Spain and Madrid will be at the center of the media coverage during that week. It's in the best interest of everybody — especially now with the economic crisis and turbulence — that Spain is shown to be able to work and to organize a big event.
So, they see this as an opportunity?
It is an opportunity. We are under difficult economic circumstances, which means that their collaboration is less in an economic sense, [but] the spirit is quite good. They are providing everything they usually provide for big events of this kind.
What advice would you give to pilgrims attending the event?
They have to be prepared in two senses: The first is the spiritual sense — the spiritual preparation, so that those who are coming will meet many people coming from all over the world, and they will experience the universality of the Church.
Our goal is to help them have a personal encounter with Jesus Christ, which means that the better prepared they arrive, the more fruitful the meeting will be for them. So I would strongly recommend they go to the sacraments, because that's the best way to encounter Jesus Christ — in the Eucharist and also confession. So, that's one way to get prepared.
The second way, I would say, depends on where you come from. But if you come from a country with little or moderate sunshine, please bring sunblock and drink a lot of water. It's going to be hot. On the one hand, Madrid is not as humid as Rome, because we're [nearly a half mile] high, but that means the heat is dry. This means you have to drink a lot of water and bring with you the right clothes etc.
You spoke about the importance of the sacraments — many have found it of interest that the Pope will hear confessions for the first time on World Youth Day.
Absolutely — and the interesting point is that when he was told that the organizing committee wanted him to hear confessions, the person who is in charge of the Pope's trips here told him: "We have decided, if you want, you can hear a few confessions."
The Pope's reaction was: "How many?" Because of time constraints, they said maybe two, three or four, and the Pope's reaction was: "Only that?!" I think it will show also how important it is that many young people discover and rediscover the value and importance of confession and frequent confession in Christian life. So I think that's a good way of putting this in front of many eyes.
And the Holy Father will also have lunch with young people?
Yes, that's a normal thing for World Youth Day. Actually, what was interesting was that we, the organizing committee, decided not to take an important role in deciding who would have this meal with the Pope. We decided to put the names of international volunteers in a hat, and a neutral hand pulled them out. Twelve have been chosen — two from each continent plus two from Spain.
One of those chosen from Spain is a girl not from Madrid, and the Madrid one is a man with disabilities.
How many pilgrims are expected?
Our calculations have been made this way: We know how many people have been registered so far, which is more or less 410,000 people plus volunteers, bishops etc. So we're around 450,000 people. And we know according to the ratios of other World Youth Days that people attending the vigil and final Mass are three times more than that.
But we don't have that information; so far, we're just saying registered people [totals] 450,000. What happens afterwards, I have no idea. We have to be prepared to have at that final Mass a million and a half.
As this is the third time Benedict XVI has been to Spain, do you think he's perhaps giving a sign?
It's a sign — a sign of how much the Pope loves Spaniards! I think there are two reasons for this: Firstly, that Spain is suffering a very intense and fast secularization process; the Church is concerned about that and wants to do something. The Pope is the first person to do something. And the second is that the Pope sometimes goes wherever he is invited. I don't think there are many dioceses in the world willing to undergo this process, because it takes a lot of time, effort and resources to organize this, so it's not for everyone.
Cardinal Ruoco was also really insisting to have this World Youth Day in Madrid because he organized the second one in 1989, in Santiago de Compostela, when he was archbishop there, and he saw great fruits. So this is his second World Youth Day, and he thought it was worthwhile.
What are your own expectations? What do you think will be the highlights for you?
I think, from a television point of view, it will be the welcome of the Pope and the Stations of the Cross, and then if the goal is to make possible a personal encounter with Jesus Christ, we will never know what happened.
We will see in the future how many people came to the Church for the first time or have a religious commitment, but that will be really difficult to evaluate — so, many of the most important things of World Youth Day will not be under the eye of the camera.
Edward Pentin writes from Rome.

subset: commoncrawl


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Our History
From the time it opened in 1940, Bi-Rite Market has been a Mission District institution.
The Mogannam family has owned the market since 1964, with brothers Ned and Jack operating it for the first 26 years. Back then it was the sort of market where neighborhood housewives could do all their daily shopping and police officers stopped by on their daily beats. Ned's sons Sam and Raph spent their childhood stocking the grocery shelves after school and on weekends, never dreaming of owning the store one day.
Sam and Raph took over the store from their father and uncle in 1997, maintaining the classic art deco façade and the original neon sign celebrated in Michael F. Crowe's book 'Deco by the Bay'. Formerly the chef/owner of his own restaurant in downtown San Francisco, Sam brought a restaurant perspective to the grocery store, focusing on genuine service above all else: when a customer walked through the door of Bi-Rite, they would be treated like a guest in our own home. As a chef, Sam insisted on stocking cooking ingredients of the highest quality, taste, and freshness. Sam renovated the space, installing a full kitchen; for the first time in the city, restaurant-quality food was available for take-out.
Bi-Rite continues to be a family affair. Sam is the owner, Raph is the head grocery buyer, Mom and Dad Mogannam still help out at the market, and several staff members have been part of the family for years, going back to the days of Sam's restaurant. Bi-Rite Market evolves along with 18th Street and Dolores Park; as a hub of relaxation, activism, and good eats, our block has become a beating heart of San Francisco!


text:
METAIRIE — Next year will come in due time.
But to Saints All-Pro guard Jahri Evans, it's not too late to do something about this season — meaning while making the playoffs would be the equivalent of threading a needle while riding a roller coaster, the team still has a vested interest in winning its remaining two games to finish 8-8, starting with Sunday's game at Dallas.
"As long as there are games to be played, there are games to be won," Evans said Monday. "No matter what the situation, you put your best foot forward. It's never too late to play well."
The Saints certainly did that Sunday with a 41-0 victory over Tampa Bay. The franchise's first shutout since 1995 kept the Saints' playoff hopes alive, but it will require 11 games breaking right this week and next.
The victory snapped a three-game losing streak, the last of which was a 52-27 loss to the New York Giants that interim coach Joe Vitt called "embarrassing." But Evans said that game had a galvanizing effect.
"What you saw last week exemplified our not letting each other down," he said. "We could have been moping around and sad over the outcome, but instead we went out there happy to be playing for each other.
"We were really loose in practice and stuff. You just knew we were going to go out there and play well."
Tampa Bay seemingly came into the game with similar motivation. Despite a three-game losing streak, at 6-7 the Buccaneers were in a better playoff position than the Saints.
But the Bucs, who jumped to a 17-0 lead when the teams met in Tampa in October and were denied a tying touchdown pass on the last play of the game to give the Saints a 35-28 win, showed little intensity.
"I don't know what happened to them," Evans said. "Maybe some of their guys tanked it. You wouldn't think they would. I can't say."
And while some players on both teams may have been motivated by individual concerns such as enhancing their value in free agency or solidifying what may be tenuous roster spots with their current team or another, defensive coordinator Steve Spagnuolo said he felt it was a collective mindset that prevailed Sunday.
"When I got a chance to talk to the players last Wednesday, I told them that our challenge would to be make the game we played yesterday not our best game," he said. "Our guys are motivated to get better in order to help our football team win."
Certainly the defense, which entered the game last in the league in total defense and 30th in points allowed, was in its best form of the season. Not only did the Buccaneers fail to score, but they had only 96 yards in the first half, were 3 of 11 in third-down situations through three quarters and forced five turnovers — four interceptions and one fumble.
But the important thing, end Cameron Jordan said, was the shutout.
"Somewhere in the fourth quarter with around six minutes left, I was jumping on the sidelines thinking this could definitely happen," he said. "This hasn't happened to me since high school, where we would get burritos for a goose egg. No burritos this time, but that's OK."
And like Evans, Jordan said finishing .500 is a priority, even if it doesn't net a playoff berth.
"I'd love to break even," he said. "We need to go to Dallas, get that and then come home and play Cam Newton and Carolina. That's definitely what it's about now — playing complete games, which is what we should have been doing all along. It's nice to see that we are able to capitalize the potential that everybody saw in us, but we should have shown it earlier."
The Saints' playoff situation is one that could hardly have been expected of a team that began the season considered a Super Bowl contender, even amid the turmoil the pay-for-performance affair created.
"It's sort of bittersweet," Evans said. "We definitely displayed yesterday what we wish we could have done a little earlier in the season. Hopefully we can finish strong and take it into next year."
Even if next year means a coaching change. According to broadcast reports Sunday, suspended coach Sean Payton and the Saints are "not close" to resolving his voided contract extension. It could result in Payton becoming a free agent after he is reinstated, scheduled for the day after the Super Bowl.
"The guys are just taking it in stride," Evans said. "We sure don't know what's going to happen, but we have confidence he'll be back next season.
"And if doesn't happen, we'll deal with it then. Right now, we're just concentrating on the Cowboys."


text:
Solving Quadratic Trig Equations (Day 1 of 2)
Lesson 10 of 16
Objective: SWBAT use their knowledge of quadratic equations to solve quadratic trig equations.
Big Idea: The class works together to review methods of solving quadratic equations and make connections to quadratic trig equations.
I begin today's class by asking students to solve the equation on slide 2 of the flipchart - Solving Quadratic Trig Equations. My goal is to get students thinking about how to solve quadratic equations using inverse operations. I am prepared to remind students that:
- They should review having to square root both sides of the equation to solve for x (MP7).
- A quadratic equation can allow 2, 1 or 0 solutions (MP6, MP7).
If possible I will avoid providing assistance to students on this warm-up problem. I want to assess who can and who cannot solve the problem independently. However, I plan to go over the problem with the class.
Resources (4)
In the middle part of today's lesson, my goal is to have students review solving quadratic equations before we move onto solving quadrtaic trigonometric equations in tomorrow's lesson. After guiding students through part 1 of the Student Activity: Solving Quadratic Trig Equations, I will have students work through exercise 1-5 in part II focusing only on the Algebraic form. then students will present their solutions. Here is more detail on how this went my first year teaching it: Solving Quadratic Trig Equations Day 1, Video Narrative, Quadratic Trig Equations
While students are working through this activity the following mathematical practice standards will be addressed: MP1, MP2, MP3, MP5, MP6, MP7, MP8.
Resources (10)
To close out today's lesson, I will ask my students to identify questions they still have about solving quadratic trigonometric equations. First, I will have students write down one question they still have (page 4 in Flipchart). Then, I will encourage students to discuss questions in their teams (page 5 in Flipchart). If questions go unanswered, I will step in and make clarifying suggestions. I want to mak sure that students arrive in a confident place before the end of class (page 6 in Flipchart).


text:
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text:
Kaze no Stigma
- Title
- Kaze no Stigma
- Genre
- Anime
- Episodes
- 1 Season, 48 Episodes
- Description
- Kazuma's clan is skilled in fire magic, but when his female cousin, Ayano, beat him in a battle to become the clan's successor, Kazuma went into exile. Now he's back with a powerful new mojo that's sure to fan the flames of the family rivalry.
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ARM Announces Extension of Commitment To The ARM Roadmap by STMicroelectronics And Licensing Of Two Advanced Microprocessor Cores
CAMBRIDGE, UK – Sept. 15, 2003 –ARM, [(LSE:ARM);(Nasdaq:ARMHY)], the industry's leading provider of 16/32-bit embedded RISC microprocessor solutions, today announced that STMicroelectronics (NYSE:STM) has extended its ARM® technology license. This extension will enable STMicroelectronics to continue to design and manufacture products based on a broad range of ARM microprocessor cores.
In addition, STMicroelectronics has licensed two of the most advanced ARM microprocessor cores, the ARM1026EJ-S™ core and the award-winning ARM1136JF-S™ core, as part of its ongoing commitment to the ARM architecture.
STMicroelectronics has been a prominent ARM Partner since its first license in 1998 for the industry-leading ARM7TDMI® core. Since then, STMicroelectronics has used ARM technology in a broad range of wireless and networking applications, and has also used ARM microprocessor cores to provide its customers with complex SoC solutions in the automotive and printer markets.
"ARM works closely with its Partners to ensure they are able to deliver innovative ARM Powered® products, and this latest agreement with STMicroelectronics enables the continued use of ARM technology in a wide range of applications," said Mike Inglis, EVP, Marketing, ARM. "STMicroelectronics' extension of their existing license is a major endorsement of ARM microprocessor technology by one of the world's leading semiconductor companies."
"STMicroelectronics technology based on the ARM architecture continues to deliver real value to our customers, and our partnership with ARM not only gives existing customers stability, but also shows where STMicroelectronics is headed in the future," said Bernard Fontan, director of Strategic Planning in ST's Telecom, Peripherals & Automotive Groups. "This new agreement provides a very good opportunity to create innovative new products that combine the latest ARM technology with our expertise in mobile communications, convergence and multimedia applications."
About ARM
ARM is the industry's leading provider of 16/32-bit embedded RISC microprocessor solutions. The company licenses its high-performance, low-cost, power-efficient RISC processors, peripherals, and system-on-chip designs to leading international electronics companies. ARM also provides comprehensive support required in developing a complete system. ARM's microprocessor cores are rapidly becoming a volume RISC standard in such markets as portable communications, handheld computing, multimedia, digital consumer and embedded solutions. More information on ARM is available at www.arm.com.
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ARM, ARM Powered and ARM7TDMI are registered trademarks of ARM Limited. ARM1026EJ-S and ARM1136JF-S are trademarks of ARM Limited. "ARM" is used to represent ARM Holdings plc (LSE: ARM and Nasdaq: ARMHY); its operating company ARM Limited; and the regional subsidiaries ARM INC; ARM KK; ARM Korea Ltd; ARM Taiwan; ARM France SAS; ARM Consulting (Shanghai) Co.Ltd.; and ARM Belgium N.V.


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Eddie Redmayne's big night out at the British Academy of Film and Television Arts (BAFTA) awards turned into a disaster after he was struck down with food poisoning.
The model-turned-actor attended the London event in support of the musical, which was up for Best Film and Outstanding British Film, and his Les Miserables co-stars Hugh Jackman and Anna Hathaway, who were nominated in the acting categories.
He told reporters that he felt ill as he walked the red carpet, and he was forced to pull out of presenting the Original Screenplay award with Lincoln star Sally Field after he began vomiting backstage.
After Anne Hathaway won the Best Supporting Actress BAFTA for her role in the film, she passed on her best wishes to the Brit, telling the audience, "Oh God, Eddie, feel better. I'd be holding your hair back but, you know... food poisoning is just the worst."


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A: Or you know what? Perhaps he deserves a day off, since the Heat then don't play again until next Thursday. Sort of give him his week off he didn't get for All-Star break. But, yes, he's already posted on Instagram photo of what he might look like in one particular mask.
February 20, 2014Q: Shouldn't we be thankful for Kevin Durant's greatness? Winning two championships in a row and going for a third consecutive title, there was a little or no motivation for LeBron James to push himself during the regular season. As pundits suggested, he was coasting in regular season, as expected. Don't get me wrong, he has put up MVP numbers. Then Russell Westbrook went down and Durant took over the show from LeBron. Seeing his place as the best player in the league threatened, LeBron is responding in a big way. We see more energy, passion, and commitment. Durant vs. LeBron is becoming a thing that makes you want to check what each player does every game. It's fun to argue who had a better night. I am not suggesting this is a rivalry already but if we at least get a glimpse of Magic vs. Larry from these two super talents, NBA basketball will be in good hands for the foreseeable future. -- Baron.
A: Wow, the "anti-cogent" spam filters apparently no longer are working in the "Ask Ira" email box. Your points are well made, and I do see some of that playing out. While there is respect between the two, there also is legitimate competition. It's what some have attempted to create between LeBron and Carmelo Anthony, with Anthony's lack of overall success somewhat limiting that equation. To a degree, we're seeing some of LeBron vs. Carmelo in the LeBron-vs.-Paul George matchups, as well. As long as the individual rivalries don't overshadow the ultimate title aspirations, they're terrific for the game.


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Study Of Oral PHA-848125AC In Patients With Malignant Thymoma Previously Treated With Multiple Lines Of Chemotherapy
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
|ClinicalTrials.gov Identifier: NCT01301391
Recruitment Status : Active, not recruiting
First Posted : February 23, 2011
Last Update Posted : July 18, 2017
- Study Details
- Tabular View
- Results Submitted
- Disclaimer
- How to Read a Study Record
|Condition or disease
|Malignant Thymoma
|Drug: Milciclib Maleate
|Phase 2
|Study Type :
|Interventional (Clinical Trial)
|Actual Enrollment :
|30 participants
|Intervention Model:
|Single Group Assignment
|None (Open Label)
|Primary Purpose:
|Official Title:
|Phase II Study Of Oral PHA-848125AC In Patients With Malignant Thymoma Previously Treated With Multiple Lines Of Chemotherapy
|Study Start Date :
|January 2011
|Estimated Primary Completion Date :
|October 2017
|Estimated Study Completion Date :
|December 2018
Experimental: Milciclib
Milciclib Maleate capsules
Drug: Milciclib Maleate
150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.
Number of cycles: until disease progression or unacceptable toxicity.
Other Name: PHA-848125AC
- Progression-free survival rate at 3 months [ Time Frame: 3 months since treatment start ]
- Adverse Events (NCI CTCAE) and hematological and blood chemistry parameters [ Time Frame: All cycles from enrollment to 28 days after last treatment ]
- Objective Response Rate (ORR) by RECIST [ Time Frame: The best confirmed objective response among all oncological assessments performed every 6 weeks from treatment start until PD. ]
- Disease Control rate (ORR+SD Rate) [ Time Frame: The best confirmed objective response among all oncological assessments performed every 6 weeks from treatment start until PD and stabilizations lasting for longer than 6 months as measured. ]
- Duration of Response [ Time Frame: The interval between the time when criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented as measured by the oncological assessments performed every 6 weeks. ]
- Overall Survival [ Time Frame: The time from the date of treatment start to the date of death from any cause or two years since treatment discontinuation -whichever comes first- as assessed every 6 weeks until PD and every 6 months after treatment discontinuation. ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:
|18 Years and older (Adult, Older Adult)
|Sexes Eligible for Study:
|Accepts Healthy Volunteers:
Inclusion Criteria:
- Signed and dated IRB/Approved Informed Consent
- Histologically or cytologically proven diagnosis of unresectable B3 thymoma or thymic carcinoma recurrent or progressing after more than one prior systemic therapy for advanced / metastatic disease
- Presence of measurable disease
- Age >=18 years old
- ECOG performance status 0-1
- Negative pregnancy test (if female in reproductive years)
- Use of effective contraceptive methods if men and women of child producing potential
- Adequate liver function Total Serum Bilirubin <=1.5 x upper limit of normal (ULN) Transaminases (AST/ALT) <=2.5ULN (if liver metastases are present, then <=5ULN is allowed) ALP <=2.5ULN (if liver and/or bone metastases are present, then <=5ULN is allowed)
- Adequate renal function Serum Creatinine <=ULN or Creatinine Clearance calculated by Cockcroft and Gault's formula > 60 mL/min
- Adequate hematologic status ANC >=1,500cells/mm3 Platelet Count >= 100,000cells/mm3 Hemoglobin >=9.0g/dL
- Two weeks must have elapsed since completion of prior chemotherapy, minor surgery, radiotherapy (provided that no more than 25% of bone marrow reserve has been irradiated)
- Resolution of all acute toxic effects of any prior treatments to NCI CTC (Version 3.0) grade <=1
Exclusion Criteria:
- Any of the following in the past 6 months: myocardial infarction, uncontrolled cardiac arrhythmia, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis
- Grade >1 retinopathy
- Known brain metastases
- Known active infections
- Pregnant or breast feeding women
- Diabetes mellitus uncontrolled
- Gastrointestinal disease that would impact on drug absorption
- Patients under treatment with anticoagulants or with coagulation disorders or with signs of hemorrhage at baseline
- Patients with previous history or current presence of neurological disorders (with the exception of myasthenia gravis), including epilepsy (although controlled by anticonvulsant therapy), Parkinson's disease and extra-pyramidal syndromes.
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that make the patient inappropriate for entry into this study
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01301391
|United States, District of Columbia
|MedStar Georgetown University Hospital
|Washington, D.C., District of Columbia, United States, 20007
|United States, Maryland
|NIH, Center for Cancer Research, Medical Oncology
|Bethesda, Maryland, United States, 20892
|Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
|Milano, (mi), Italy, 20133
|Study Director:
|Anna Petroccione, MD
|CLIOSS (Nerviano Medical Sciences Group), Italy
|Principal Investigator:
|Arun Rajan, MD.
|National Cancer Institute (NCI)
|Principal Investigator:
|Marina C. Garassino, MD.
|Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
|Principal Investigator:
|Giuseppe Giaccone, MD
|MedStar Gergetown University Hospital
|Responsible Party:
|Tiziana Life Sciences, PLC
|ClinicalTrials.gov Identifier:
|NCT01301391 History of Changes
|Other Study ID Numbers:
|First Posted:
|February 23, 2011 Key Record Dates
|Last Update Posted:
|July 18, 2017
|Last Verified:
|July 2017
Keywords provided by Tiziana Life Sciences, PLC:
B3 and C malignant thymoma
Additional relevant MeSH terms:
Thymus Neoplasms
Neoplasms, Complex and Mixed
Neoplasms by Histologic Type
Thoracic Neoplasms
Neoplasms by Site
Lymphatic Diseases
Maleic acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action


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Most Plastic Products Release Estrogenic Chemicals: A Potential Health Problem That Can Be Solved
[do action="authors"]Chun Z. Yang1, Stuart I. Yaniger2, V. Craig Jordan3, Daniel J. Klein2, George D. Bittner1,2,4[/do][do action="affiliations"]1 CertiChem Inc., Austin, Texas, USA, 2 PlastiPure Inc., Austin, Texas, USA, 3 Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA, 4 Neurobiology Section, School of Biology, University of Texas, Austin, Texas, USA[/do][do action="citation-string"]Environ Health Perspect 119:989-996 (2011). http://dx.doi.org/10.1289/ehp.1003220 [online 02 March 2011] [/do]
[do action="abstract"]
Background: Chemicals having estrogenic activity (EA) reportedly cause many adverse health effects, especially at low (picomolar to nanomolar) doses in fetal and juvenile mammals.
Objectives: We sought to determine whether commercially available plastic resins and products, including baby bottles and other products advertised as bisphenol A (BPA) free, release chemicals having EA.
Methods: We used a roboticized MCF-7 cell proliferation assay, which is very sensitive, accurate, and repeatable, to quantify the EA of chemicals leached into saline or ethanol extracts of many types of commercially available plastic materials, some exposed to common-use stresses (microwaving, ultraviolet radiation, and/or autoclaving).
Results: Almost all commercially available plastic products we sampled—independent of the type of resin, product, or retail source—leached chemicals having reliably detectable EA, including those advertised as BPA free. In some cases, BPA-free products released chemicals having more EA than did BPA-containing products.
Conclusions: Many plastic products are mischaracterized as being EA free if extracted with only one solvent and not exposed to common-use stresses. However, we can identify existing compounds, or have developed, monomers, additives, or processing agents that have no detectable EA and have similar costs. Hence, our data suggest that EA-free plastic products exposed to common-use stresses and extracted by saline and ethanol solvents could be cost-effectively made on a commercial scale and thereby eliminate a potential health risk posed by most currently available plastic products that leach chemicals having EA into food products.
[/do][do action="abstract"]Key words: bisphenol A, endocrine disruptor, endocrine-disrupting chemical, estrogen receptor binding, estrogenic activity, plastic[/do]
[do action="notes-rule-above"]Address correspondence to G.D. Bittner, CertiChem, Inc., 11212 Metric Blvd., Suite 500, Austin, TX 78758 USA. Telephone: (512) 339-0550, ext. 201; Fax: (512) 339-0551. E-mail: email@example.com[/do][do action="notes"]This work was supported by National Institutes of Health (NIH) grants R44 ES011469 (01-03) and 1R43/44 ES014806 (01-03) to C.Z.Y.; R44 ES016964 (01-03) to S.I.Y.; and P30 CA051008 to V.C.J.[/do][do action="notes"]C.Z.Y. is employed by, and owns stock in, CertiChem (CCi) and PlastiPure (PPi). S.I.Y. and D.J.K. are employed by PPi. V.C.J. has no financial interests in CCi or PPi, but he was principal investigator for a subcontract at Northwestern Medical School to help develop the MCF-7 assay on NIH grant P30 CA051008 awarded to CCi. G.D.B. owns stock in, and is the founder and chief excutive officer of CCi and the founder and chief scientific officer of PPi. All authors had freedom to design, conduct, interpret, and publish research uncompromised by any controlling sponsor.[/do][do action="notes"] Received 16 November 2010; accepted 24 February 2011; online 02 March 2011.[/do]
Chemicals that mimic or antagonize the actions of naturally occurring estrogens are defined as having estrogenic activity (EA), which is the most common form of endocrine disruptor activity [Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) 2003, 2006; National Research Council 1999]. Chemicals having EA typically interact with one or more of the classical nuclear estrogen receptor (ER) subtypes: ERα, ERβ, or nonclassical membrane or ER-related subtypes (Hewitt et al. 2005; Matsushima et al. 2008; National Research Council 1999). In mammals, chemicals having EA can produce many health-related problems, such as early puberty in females, reduced sperm counts, altered functions of reproductive organs, obesity, altered sex- specific behaviors, and increased rates of some breast, ovarian, testicular, and prostate cancers (Della Seta et al. 2006; Gray 2008; Kabuto et al. 2004; National Research Council 1999; Newbold et al. 2004; Patisaul et al. 2006, 2009). Fetal, newborn, and juvenile mammals are especially sensitive to very low (sometimes picomolar to nanomolar) doses of chemicals having EA (Gray 2008; vom Saal et al. 2005). Many of these effects observed in mammals are also expected to be produced in humans, because basic endocrine mechanisms have been highly conserved across all classes of vertebrates (Kavlock et al. 1996; National Research Council 1999).
Thermoplastics, which are used for many items that contain food, are made by polymerizing a specific monomer or monomers in the presence of catalysts into a high-molecular- weight chain known as a thermoplastic polymer [see Supplemental Material, Figure 1 (doi:10.1289/ehp.1003220)]. The resulting polymer is mixed with small quantities of various additives (antioxidants, plasticizers, clarifiers, etc.) and melted, mixed, extruded, and pelletized to form a base thermoplastic resin. Base resins are either used as is [e.g., bisphenol A (BPA)-based polycarbonate (PC), non-BPA-based polypropylene (PP) copolymer (PPCO), and non-BPA-based PP homopolymer (PPHO)] or, more commonly, mixed with other resins, additives, colorants, and/or extenders to form plastic compounds (e.g., polymer blends and precolored polymers). Plastic products are then made by using one or more plastic compounds or resins to form a finished plastic part that can be subjected to finishing processes that may use inks, adhesives, and so forth, to make a finished product.
Results of MCF‑7 assays shown as dilution response curves (%E2) for E2 (A), E2 and BPA (B), BHA (C), and %RME2 of extracts of plastic bags (D), a PC bottle (E), and a BPA-free bottle made from PETG (F). Abbreviations: PETG, PET glycol-modified polyethylene terephthalate; VC, vehicle control. Dotted lines represent 3 SD from the response. In B–F, the negative control (1% EtOH or saline) equals 0% E2. The E2 standard (10–9 M) is the positive control diluted as indicated in C–F. Each point plotted is the average of three or four replicates for each concentration whose SD is very small and falls within the space taken up by each data point. In (A), E2 was dissolved in EtOH (standard extract) or concentrated 10× and rediluted to show that the EtOH concentration protocol has very little effect on the EC50 of E2 (50% E2). The EC50 of E2 is approximately 1.3 × 10–13 M, and the threshold of detection (15% E2) is approximately 10–15 M. The maximum E2 response was attained at 10–11 M and remained constant at higher E2 concentrations. (B) The EC50 of both E2 (as in A) and BPA is approximately 6.6 × 10–8 M, and threshold detection is approximately 10–9 M, all suppressed by 10–8 M ICI. (C) BHA does not meet criteria needed for accurate calculation of EC50 [see Supplemental Material, pp. 5–7 (doi:10.1289/ehp.1003220)]. EA is positive; its maximum response is about 50% E2 (i.e., 50% RME2) and is suppressed by 10–8 M ICI. In D, commercially available plastic bags were extracted by 100% EtOH. Commercially available PC (E) and BPA-free (F) bottles were extracted with saline or EtOH as indicated.
As previously described (Begley et al. 1990, 2005; De Meulenaer and Huyghebaert 2004), plastic resins and manufacturing protocols [see Supplemental Material, Figure 1 (doi:10.1289/ehp.1003220)] collectively use many monomers and additives that may exhibit EA because they have physicochemical properties, often from an insufficiently hindered phenol (HP) group, that enable them to bind to ERs (see Supplemental Material, Table 1). Because polymerization of monomers is rarely complete and additives are not chemically part of the polymeric structure, chemicals having EA can leach from plastic products at very low (e.g., nanomolar to picomolar) concentrations that individually or in combination can produce adverse effects, especially in fetal to juvenile mammals. This leaching of monomers and additives from a plastic item into its contents is often accelerated if the product is exposed to common-use stresses such as ultraviolet (UV) radiation in sunlight, microwave radiation, and/or moist heat via boiling or dishwashing. The exact chemical composition of almost any commercially available plastic part is proprietary and not known. A single part may consist of 5–30 chemicals, and a plastic item containing many parts (e.g., a baby bottle) may consist of ≥ 100 chemicals, almost all of which can leach from the product, especially when stressed. Unless the selection of chemicals is carefully controlled, some of those chemicals will almost certainly have EA, and even when using all materials that initially test EA free, the stresses of manufacturing can change chemical structures or create chemical reactions to convert an EA-free chemical into one with EA.
Percentage of unstressed plastic products having EA in at least one extract.
Very few studies (Soto et al. 1991; Till et al. 1982) have examined the extent to which plastics that presumably do not contain BPA nevertheless release other chemicals having detectable EA. For example, a recent comprehensive review [table on page 72 of Gray (2008)] described polyethylene (PE), PP, and PE terephthalate (PET) plastics as being "'OK' for use with respect to release of chemicals exhibiting EA."
Here, we report that most of the > 500 commercially available plastic products that we sampled—even those that are presumably BPA free—release chemicals having detectable EA, especially if they are assayed by more polar and less polar solvents and exposed to common-use stresses. That is, we show that, to reliably detect such leachable chemicals having EA, unstressed or stressed plastic resins or products should be extracted with more polar (e.g., saline) and less polar [e.g., ethanol (EtOH)] solutions and exposed to common-use stresses (boiling water, microwaving, and UV radiation).
Materials and Methods
We developed a sensitive and accurate roboticized version of the MCF-7 cell proliferation assay (E-SCREEN assay) that has been used for decades to reliably assess EA and anti-EA (Leusch et al. 2010; Soto et al. 1995) and is currently undergoing validation for international use by ICCVAM/NTP (National Toxicology Program) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). Chemicals with EA bind to ERs (ERα, ERβ, or ER-related subtypes) and activate the transcription of estrogen-responsive genes, which leads to proliferation of MCF-7 cells.
Detailed methods for the MCF-7 assay are provided in Supplemental Material, (doi:10.1289/ehp.1003220). In brief, plastic resins or products were extracted using saline, a more polar solvent, or EtOH, a less polar solvent. Aliquots of the extracts were then diluted four to eight times to produce up to eight test concentrations. Each test chemical or extract at each concentration was added in triplicate or quadruplicate to 96-well plates containing MCF-7 cells in EA-free culture media. After 6 days of exposure, the amount of DNA per well, an indication of cell proliferation, was assayed using a microplate modification of the Burton diphenylamine assay (Burton 1956; Natarajan 1994).
The effect of a test chemical or extract on proliferation was expressed as the %E2, a percentage of the maximum DNA per well produced by the maximum response to 17β-estradiol (E2; positive control) corrected by the DNA response to the vehicle (negative) control [see Supplemental Material, Equation 1 (doi:10.1289/ehp.1003220)]. For estrogenic test chemicals, the concentration needed to obtain half-maximum stimulation of cell proliferation [half-maximal effective concentration (EC50), a measure of binding affinity] was calculated from best fits to dose–response data that meet a well-defined set of criteria by Michaelis-Menton kinetics. The estrogenicity of extracts was calculated as the relative maximum %E2 (%RME2; a measure of response amplitude), a percentage of the maximum DNA per well produced by an extract at any dilution with respect to the maximum DNA per well produced by E2 at any dilution, corrected by the DNA response to the vehicle (negative) control (see Supplemental Material, Equation 2). If a test chemical had a positive response (> 15% RME2) but an EC50 could be calculated because not all criteria were met, then the estrogenicity of the test chemical was characterized simply as EA positive or by its %RME2.
The EA of a test chemical or extract was considered detectable if it produced cell proliferation > 15% of the maximum response to E2 (> 15% RME2), which is > 3SDs from the historic control baseline response (about 10–15 M), which is a rather conservative measure of EA detectability. Stimulation of MCF-7 proliferation induced by the test chemical or extract was confirmed to be estrogenic (compared with nonspecific) in an EA confirmation study: If the stimulation of MCF-7 proliferation by a test chemical or extract was suppressed by coincubation with a strong antiestrogen [ICI 182,780 (ICI) at 10–7 to 10–8 M], the EA of the test chemical or extract was confirmed. Therefore, a test chemical or extract was classified as not having detectable EA if it did not induce MCF-7 cell proliferation or if it induced proliferation that could not be inhibited by ICI.
Figure 1 shows typical MCF-7 responses plotted as %E2. Figure 1A–C show responses to some test chemicals: E2 (positive control), BPA, and butylated hydroxyanisole (BHA; a common antioxidant). Figure 1D–F show %RME2 responses to test extracts of plastic food bags, PC bottles, and BPA-free baby bottles and their ICI-suppressed responses, confirming their EA. Some chemicals or products were also analyzed for anti-EA [for details, see Supplemental Material, pp. 7–8 (doi:10.1289/ehp.1003220)].
Purchase and analyses of plastic products in survey studies. For Tables 1 and 2, we purchased 455 plastic products used to contain foodstuffs from various commercial retailers from 2005 through 2008. The relative frequency of products having detectable EA did not change with later compared with earlier purchases. In some cases, we instructed undergraduate students or employees to purchase a mix of plastic items used to contain foodstuffs from a given large retailer (Albertsons, H-E-B, Randalls, Target, Wal-Mart, Trader Joe's, and Whole Foods) mainly in the Austin, Texas, or Boston, Massachusetts, areas, some of which market many "organic" products. In other cases, we purchased products of a particular plastic type (e.g., PE- or PP-based containers). We recorded the retailer, resin type [high-density PE (HDPE), PET, PC, PP, polystyrene (PS), polylactic acid], and product type (flexible packaging, food wrap, rigid packaging, baby bottle component, deli containers, plastic bags). In addition, because the contents of some plastic items might have added or extracted chemicals having EA from the plastic containers before we purchased and tested the products (Sax 2010), we recorded whether the plastic items had contents or were empty when purchased. For any plastic container having contents, we thoroughly washed out the container with distilled water before testing the plastic. Except for PC-based items, none of these products were known to contain BPA. (Plastic products typically do not list their chemical composition, which is proprietary to the manufacturer.) Samples were chosen in product areas where adverse health effects might occur if the samples leached chemicals having EA. Samples from each retailer generally included most of the product types listed above. In addition to surveying commercially available products, we tested plastic resins [e.g., PC, PET, glycol-modified PET (PETG)] that were purchased from M. Holland Company (Northbrook, IL) and individual chemicals used to manufacture plastic products [e.g., BPA, BHA, butylated hydroxytoluene (BHT), dimethyl terephthalate, etc.] that were purchased in their purest form from Sigma-Aldrich (St. Louis, MO).
Percentage of unstressed plastic products having detectable EA (> 15% RME2) in two extracts.
Many plastic products have more than one plastic part. For example, baby bottles have 3–10 different plastic parts in various combinations [bottle, nipple, anticolic item(s), sealing ring(s), liner bag, cap, etc.], each part typically having different and rather unique combinations of 5–30 chemicals. Over the course of this entire study, we assayed > 100 component parts from > 20 different baby bottles, including many advertised as BPA free. Only some (13) of these component parts were purchased for the initial survey study (Tables 1 and 2).
Most of the samples (338 of 455) in the survey study (Tables 1 and 2) were extracted using only one extraction protocol. For the remaining samples (n = 102), both saline and EtOH extractions were used so that the efficacy of each protocol could be directly compared. We used a paired Student's t-test to test whether differences between pairs of samples were statistically significant (p < 0.05).
Protocols for common-use stresses of some plastic items. Given that common-use stresses can alter the complex chemical composition of plastics and/or increase the rate of leaching (Begley et al. 1990, 2005; De Meulenaer and Huyghebaert 2004), for some resins or products, we examined how leaching of chemicals having EA might be affected by exposure to microwave radiation, autoclaving (moist heat), and UV light. Additional plastic items, some of which are described in Figure 2 and Table 3, were purchased in 2008–2010 and subjected to common-use stresses. In addition, we tested a variety of resins (including PE- and PP-based resins; Table 3), antioxidants [see Supplemental Material, Table 3 (doi:10.1289/ehp.1003220)], and other additives or processing agents (see Supplemental Material, Table 4) identified by our laboratory as being free of detectable EA and hence possibly suitable for use to produce final products that would be EA free even after exposure to common-use stresses.
Total EA released by some PC and BPA-free water bottles (W) and baby bottles (B). The leaching of chemicals having EA (measured as %RME2; excluding caps, nipples, and other components) were extracted using saline or EtOH as solvents and exposed to autoclaving, microwaving, and/or UV light (see "Materials and Methods" for details). BPA-free water bottles W1, W2, W3, and W4 are PETG, and W5 is PET. BPA-free baby bottles B1 and B2 are polyethersulfone; B3 is PETG; and B4 and B5 are PP. Orange bars indicate the data set for each individual product. The %RME2 for saline extracts is represented by solid black lines and for EtOH as solid red lines. Symbols represent the %RME2 of chemicals released by each assay of a product after an autoclaving stress, microwaving stress, and UV light stress (see figure key). The dotted horizontal line at 15% RME2 is the rather conservative value below which EA was considered nondetectable (ND) for any assay. For some products shown (e.g., PC B1, BPA-free B4), if one solvent and/or stress condition showed reliably detectable EA, other solvents and stress conditions were not subsequently tested. Some values plotted as 0% RME2 actually had slightly negative %RME2 values (–1% to –7% RME2) due to cellular toxicity.
Representative %RME2 values for stressed resins or parts made from flexible or HC polymers.
We used the following stresses:
- Samples were placed about 2 feet from a 254-nm fluorescent fixture for 24 hr, simulating repeated UV stress by sunlight (e.g., water bottles) or UV sterilizers (e.g., baby bottles and medical items)
- Samples were autoclaved at 134°C for 8 min, simulating moist heat stress in an automatic dishwasher
- We heated samples in a microwave 10 times for 2 min each, using a 1,000-W kitchen microwave oven set to "high," simulating heat and microwave radiation stress to reusable food containers.
Release of chemicals having EA from unstressed plastics. Tables 1 and 2 show the percentage of samples in each category that had reliably detectable EA (> 15% RME2) in our survey of 455 commercially available plastic products. [For the %RME2 and content status of individual samples, as well as the average %RME2 for products classified by resins (HDPE, PP, PET, PS, polylactic acid, PC), product type (flexible packaging, food wrap, rigid packaging, baby bottle components, plastic bags), and retailer (large retailers 1–5 and large organic retailers 1 and 2), see Supplemental Material, Table 5 (doi:10.1289/ehp.1003220).] For example, 9 of 13 HDPE plastic products extracted by our standard EtOH protocol (69%) had detectable EA (Table 1), with a %RME2 (mean ± SD) of 66% ± 25% (see Supplemental Material, Table 5A). For PET products extracted by saline, 26 of 34 (76%) had detectable EA (Table 1) with a %RME2 of 64% ± 41% (see Supplemental Material, Table 5C). We found no consistent correlation between the percentage of items in a product type with detectable EA and their mean %RME2 (data not shown).
We found no significant difference (p > 0.05) in the percentage of items with detectable EA between those with contents and those with no contents (76%, n = 160) at the time of purchase based on the standard EtOH extraction protocol [67% vs. 70%; see Supplemental Material, Table 2A (doi:10.1289/ehp.1003220)], the standard saline protocol (62% vs. 75%; see Supplemental Material, Table 2C), or all extraction protocols combined (69% vs. 76%). Most important, items with no contents in all categories exhibited detectable EA in at least one protocol (see Supplemental Material, Tables 2 and 5), including 78% of items made from HDPE (n = 18), 57% from PP (n = 14), and 100% from PET (n = 6). Given all of these results, we present the data for all items shown in Tables 1 and 2 without regard to their content status.
Using different solvents increased the probability of detecting EA. Most (71%) unstressed plastic items released chemicals with reliably detectable EA in one or more extraction protocols, independent of resin type, product type, or retailer (Table 1). Results often differed between saline and EtOH extracts of the same unstressed plastic item, and EA was reliably detected most frequently (92% of all items listed in Table 2) when analyzed using both saline (more polar) and EtOH (less polar) extracts. For example, 15% of unstressed HDPE plastic items leached chemicals with detectable EA into both EtOH and saline extracts, 15% leached only into EtOH, and 31% leached only into saline (Table 2). That is, the leaching of a chemical with EA was significantly (p < 0.01) more likely to be detected if we used both polar and nonpolar solvents (61%) than if we used only one solvent (30% for EtOH only or 45% for saline only). We obtained similar results for all types of plastic products (data not shown).
Assays of > 100 component parts from > 20 different baby bottles, including many advertised as BPA free, indicated that extracts of at least one bottle component of each baby bottle always had EA based on at least one assay (some data shown in Table 2 and Figure 2), as did at least one other component part (data not shown).
Stresses increased the release of chemicals having EA. Leaching of chemicals with EA was increased by common stresses. For example, one unstressed sample of an HDPE resin (P5 in Table 3) that had no detectable EA (i.e., RME2 < 15%) in two saline extracts and two EtOH extracts released chemicals with EA equivalent to 47% RME2 when extracted using EtOH after the resin was stressed with UV light. Similarly, two samples of low-density PE resins (LDPE resins 1 and 2) and PETG resins (PETG baby bottle and PETG resin 1) that had no detectable EA before stressing subsequently exhibited EA when stressed, especially by UV (Table 3). Samples (n > 10) of products made from PETG resins advertised as BPA free all released detectable EA when stressed, especially by UV light. Similarly, 25% of unstressed samples of PET and 50% of unstressed PS products surveyed did not have detectable EA in assays of EtOH and/or saline extracts (Table 1). However, when stressed and assayed using both saline and EtOH extracts, all PET (n > 10) and PS (n > 10) products released chemicals having detectable EA in at least one extracting solvent (Table 3).
EA-containing and EA-free monomers. Polymerization of monomers is rarely complete, and unpolymerized monomers are almost always released from polymer resins (Begley et al. 1990, 2005; De Meulenaer and Huyghebaert 2004). PE and PP polymers are often used to manufacture flexible and/or nontransparent rigid products (Figure 3). MCF-7 assays (n = 6) consistently showed that extracts of "barefoot" (no additives) polymers (e.g., LDPE resin P1 in Table 3) were EA free, even when stressed. (PP-based polymers require antioxidants to prevent severe degradation during their use in manufacturing plastic products.) Furthermore, PE- and PP-based resins containing appropriate additives to produce fit-for-use products could be constructed that remained EA free (n > 100 assays of > 10 resins), even when exposed to common-use stresses. Representative data from several such resins (LDPE resin P1, HDPE resin P2, PP homopolymer resin P3, PP copolymer resin P4) are shown in Table 3.
Properties of monomers and polymers used to make common resins.
Figure 3 also shows other monomers and polymers that can or cannot be used to make hard-and-clear (HC) plastics. For example, HC PC plastics (n > 10) all released chemicals having EA (e.g., PC baby bottle B1 and PC water bottle W1 in Figure 2), almost certainly phenolics such as BPA (Figure 1B). The dimethyl terephthalate monomer used to make PET and PETG plastics exhibited anti-EA (n = 3 assays; data not shown; for anti-EA assay protocol, see Supplemental Material (doi:10.1289/ehp.1003220)]. Furthermore, breakdown products of dimethyl terephthalate, PET, and PETG resins probably contain and release phenolic moieties that have EA that account for some of the data for PET products in Tables 1 and 2. Polyethersulfone HC products also consistently released chemicals having EA or anti-EA, especially when stressed with UV light (data not shown), possibly from unreacted phenolic monomer residues or phenolic stress-degradation products. In contrast, some HC cyclic olefin polymer/cyclic olefin copolymer polymers produced from saturated cyclic olefin monomers contained no phenolics and did not release chemicals having detectable EA, even when stressed (Table 3).
Polymers that can be made EA free have a similar cost compared with polymers made from monomers that have EA. For example, currently, clarified PP having no additives that exhibit EA (even when stressed) that is suitable for molding bottles costs approximately $1.20/lb. PP resins containing additives that have EA also cost about $1.20/lb. Commodity resins such as PET, which are made from monomers having EA and are suitable for molding bottles, are priced at approximately $1.28/lb (Plastics News 2011).
EA-containing and EA-free additives. Many additives are physically, but not chemically, bound to a polymeric structure and hence can almost always leach from the polymer, especially when stressed (Begley et al. 1990, 2005; De Meulenaer and Huyghebaert 2004). Antioxidants are the most critical class of additives because they prevent or minimize plastic degradation due to oxidation that breaks polymer chains (chain scission) and/or causes cross-links (Kattas et al. 2000). The oldest and most common antioxidants deemed suitable for food contact belong to a chemical class known as HPs (hindered phenols), such as BHT and BHA, in large part because both are inexpensive and assumed to be nontoxic. However, BHT (n = 4 assays) had reliably detectable EA, as did BHA (n = 3 assays). [The EC50 of BHT and BHA (Figure 1C) could not be accurately calculated because both also exhibited cellular toxicity at higher concentrations (10–5 M).] Other commonly used HP antioxidants (n = 4/5) and organophosphines (n = 6/7) also exhibited reliably detectable EA, especially when exposed to moist heat, which presumably causes hydrolysis (data not shown). For example, proprietary antioxidants Phos (phosphate) OX 1 and HP AOX 2 had no detectable EA, whereas HP AOX 1 and Ph (bisphenol) AOX 1 had reliably detectable EA [see Supplemental Material, Table 3 (doi:10.1289/ehp.1003220)].
Many other additives (n > 50) with a phenolic group had reliably detectable EA, such as agents found in many base resins [tris(nonylphenyl) phosphite, octylphenol, nonylphenol, butylbenzene phthalate], colorants (especially blues or greens with phthalocyanine groups), PS-based purge compounds, and mold-release agents [see Supplemental Material, Table 4 (doi:10.1289/ehp.1003220)]. In contrast, many metal- oxide–based inorganic pigments did not exhibit EA. However, these EA-free pigments are often mixed with dispersing agents and carrier resins that have EA to produce colorant masterbatch concentrates. Nevertheless, we have identified resins, dispersants, pigments, and antioxidants that are approved by the Food and Drug Administration for direct food contact (see Supplemental Material, Tables 3 and 4) to create colorant masterbatch concentrates (n > 100) that produce even colorant dispersion into plastics and that have no detectable EA, cellular toxicity, or adverse processing effects, even when stressed.
Because additives comprise a small fraction (typically 0.1–1% by weight) of plastic resins and compounds and because plastic resins and compounds using EA-free additives are processed during manufacture in a nearly identical manner as conventional resins and compounds containing chemicals with EA, the replacement of additives having EA with EA-free additives should have very little impact on the cost of the final product. Furthermore, EA-free additives have only a slightly higher or no additional cost compared with additives with EA, so that their cost impact is very small or nonexistent.
Products currently marketed as BPA free are not EA free. In response to market and regulatory pressures to eliminate BPA in HC plastics, BPA-free HC materials have recently been introduced as replacements for PC resins. PET and PETG are two such resins, but HC plastic products made from these resins leached chemicals that had detectable EA (Tables 1–3, Figures 2 and 3), often in the absence of exposure to common-use stresses. Two popular brands of water bottles made from a PETG resin now marketed as an HC BPA-free replacement also released chemicals having significant EA (W1, W2, W3, and W4; Table 3, Figures 2 and 3), as did uncompounded PETG resins (Table 3). Most PE/PP-based plastic products were presumably BPA free but nevertheless had readily detectable EA (Tables 1 and 2), almost certainly due to one or more additives having EA. Many components of BPA-free baby bottles had reliably detectable EA (22–95% RME2) when extracted in either saline or EtOH, including the bottle, nipple, anticolic device, and liner (data not shown).
In fact, all BPA-replacement resins or products tested to date (n > 25) released chemicals having reliably detectable EA (data not shown), including polyethersulfone and PETG, sometimes having more total EA measured as %RME2 than many PC products when stressed. For example, the %RME2 released by various BPA-free baby and water bottle component parts extracted by saline or EtOH solutions and exposed to one or more common-use stresses can be greater than PC products under the same conditions (Figure 2). UV stress, in particular, often leads to the release of chemicals having greater EA than BPA-containing HC plastics currently sold. For example, saline extracts of BPA-free baby bottle B3 (Figure 2) after exposure to UV showed greater EA than did any of the PC baby bottle extracts after any of the stresses. Saline extracts from BPA-free baby bottle B1 after any of the stresses (microwave, autoclave, or UV) showed greater EA than did the saline extracts from PC baby bottle B2 after any of the stresses. EtOH extracts from BPA-free baby bottle B1 after UV stress showed greater EA than extracts from PC baby bottle B1. Saline extracts from BPA-free baby bottle B2 after microwave or autoclave stresses showed greater EA than did saline extracts from PC baby bottles B1 or B2 after any of the stresses. Note also in Figure 2 that multiple extracts of the same product using the same solvent/stress combination typically gave rather similar %RME2 data, but different solvent/stress combinations gave very different results, from very high EA to nondetectable EA. For example, EtOH extracts from PC baby bottle B2 showed very high EA under all stress conditions, whereas saline extracts of the same bottle under the same stress conditions showed no detectable EA. Hence, to reliably detect EA, plastic resins or products must be extracted with both polar and nonpolar solvents and exposed to common-use stresses.
Most plastic products release chemicals having EA. Our data show that both more polar (e.g., saline) and less polar (e.g., EtOH) solvents should be used to extract chemicals from plastics because the use of only one solvent significantly reduces the probability of detecting chemicals having EA. The ability to detect more polar and less polar chemicals having EA is important because plastic containers may hold either type of liquid or a liquid that is a mixture of more polar and less polar solvents (e.g., milk). When both more polar and less polar solvents are used, most newly purchased and unstressed plastic products release chemicals having reliably detectable EA independent of the type of resin used in their manufacture, type of product, processing method, retail source, and whether the product had contents before testing. However, the lack of significant difference in average percentage having detectable EA between plastic items with and without contents does not imply that the contents do not affect the total EA or specific chemicals having EA released by individual plastic items.
Our data show that most monomers and additives that are used to make many commercially available plastic items exhibit EA. Even when a "barefoot" polymer (no additives) such as PE or polyvinyl chloride does not exhibit EA, commercial resins and products from these polymers often release chemicals (almost certainly additives) having EA.
We found that exposure to one or more common-use stresses often increases the leaching of chemicals having EA. In fact, our data suggest that almost all commercially available plastic items would leach detectable amounts of chemicals having EA once such items are exposed to boiling water, sunlight (UV), and/or microwaving. Our findings are consistent with recently published reports that PET products release chemicals having EA (Wagner and Oehlmann 2009) and that different PET products leach different amounts of EA. For example, different PET products release different amounts of EA measured as %E2 or %RME2 [see Supplemental Material, Table 5C (doi:10.1289/ehp.1003220)], almost certainly because different PET copolymer manufacturers choose different monomers, additive packages, and synthetic processes to produce PET copolymer resins.
Our data are consistent with the hypotheses that the presence of a phenolic moiety is the best predictor of whether a chemical exhibits EA and that benzene moieties often probably convert to phenolic moieties when the monomer and/or polymer is exposed to one or more manufacturing or common-use stresses. For example, although in theory most organophosphites (antioxidants commonly used with HPs to provide synergistic oxidation protection) in their unaltered state should not bind to ERs [see Supplemental Material, Table 1 (doi:10.1289/ehp.1003220)], organophosphites are hydrolytically unstable and often produce phenols when exposed to water (Kattas et al. 2000). Most organophosphite antioxidants we tested exhibited detectable EA (data not shown).
Likewise, various additives that are high-molecular-weight HPs do not have EA, but if exposed to moist heat they can undergo hydrolysis and produce lower-molecular-weight phenolics that have EA. Therefore, antioxidants and other additives should be tested for EA both in their original, unstressed form and after stressing. We can identify monomers and additives (antioxidants, clarifiers, slip agents, colorants, inks, etc.) having no detectable EA for use at all stages of manufacturing processes to make flexible nontransparent or HC plastic items that are EA free, even after exposure to common-use stresses. All of our data suggest that, when both are manufactured in comparable quantities, carefully formulated EA-free plastic products could have all the fit-for-use properties of current EA-releasing products at minimal additional cost.
BPA free is not EA free. Although most items listed in Tables 1–3 would not be expected to contain BPA, nevertheless almost all stressed plastic items tested leached chemicals having reliably detectable EA measured as %RME2 if extracted with both more polar and less polar solvents. In response to market and regulatory pressures, BPA-free PET or PETG resins and products have recently been introduced as replacements for PC resins. However, all such replacement resins and products tested to date release chemicals having EA (measured as %RME2), sometimes having more EA than BPA-containing PC resins or products, especially when stressed by UV light (Figure 2, Table 3). Monomer or polymer breakdown products that have EA account for some of this EA, but the rest of the measured EA is almost certainly due to release of additives having EA in BPA-free products, including the bottle and many component parts of baby bottles advertised as BPA free.
Avoiding a potential health problem. We recognize that we quantitatively measured EA relative to E2 (EC50 or %RME2) using sensitive assay and extraction protocols. Furthermore, it is almost impossible to gauge how much EA anyone is exposed to, given such unknowns as the number of chemicals having EA, their relative EA, their release rate under different conditions, and their metabolic degradation products or half-lives in vivo. In addition, the appropriate levels of EA in males versus females at different life stages are currently unknown. Nevertheless, a) in vitro data overwhelmingly show that exposures to chemicals having EA (often in very low doses) change the structure and function of many human cell types (Gray 2008); b) many in vitro and in vivo studies document in detail cellular/molecular/systemic mechanisms by which chemicals having EA produce changes in various cells, organs, and behaviors (Gray 2008); and c) recent epidemiological studies (Gray 2008; Koch and Calafat 2009; Meeker et al. 2009; Swan et al. 2005; Talsness et al. 2009; Thompson et al. 2009) strongly suggest that chemicals having EA produce measurable changes in the health of various human populations (e.g., on the offspring of mothers given diethylstilbestrol, or sperm counts in Danish males and other groups correlated with BPA levels in body tissues).
Many scientists believe that it is not appropriate to bet our health and that of future generations on an assumption that known cellular effects of chemicals having EA released from most plastics will have no severe adverse health effects (Gray 2008; Talsness et al. 2009; Thompson et al. 2009). Because we can identify existing, relatively inexpensive monomers and additives that do not exhibit EA, even when stressed, we believe that plastics having comparable physical properties but that do not release chemicals having detectable EA could be produced at minimal additional cost.
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Clarivate Analytics released the 2018 Journal Citation Reports, which tracks citations for articles published in 2015 and 2016. EHP's new Journal Impact Factor is 8.31, with a 5-Year Journal Impact Factor of 9.81. (more…)
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Some tragic news with a twist comes to us from the long holiday weekend, as we get word that a helmetless rider from Onondaga, NY died after crashing his 1983 Harley Davidson motorcycle during a protest rally.
Though it's always unfortunate when we lose a member of the motorcycle community, this story has a bit of irony as we learn that Philip A. Contos was participating in a motorcycle helmet protest when the 55-year-old flipped over the handlebars of his motorcycle, and hit his head against the pavement.
According to the attending physician, and based off the evidence and information at the scene of the accident, Contos would have survived the fall had he been wearing a DOT approved helmet, but instead sadly perished from his injuries.


text: It's no surprise that the bestselling Ash Virgin Boot is a customer favourite. Crafted from super soft premium leather this style features signature Ash detailing, with a four buckle closure and metal hardware they're the ultimate off-duty essential. Perfect for channelling a sports luxe vibe, we love them for their effortless everyday appeal.